ORCID Profile
0000-0002-8167-4917
Current Organisation
Florey Institute of Neuroscience and Mental Health
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biomedical Engineering | Biomaterials | Biochemistry and Cell Biology | Cellular Interactions (Incl. Adhesion, Matrix, Cell Wall) | Analytical Biochemistry | Computer Software not elsewhere classified | Nanotechnology | Analytical Spectrometry | Biomedical Engineering Not Elsewhere Classified | Cell Neurochemistry
ANZSRC Socio-Economic Objective (SEO)
Nervous system and disorders | Polymeric materials (e.g. paints) | Neurodegenerative Disorders Related to Ageing | Application Software Packages (excl. Computer Games) | Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified | Health related to ageing | Expanding Knowledge in the Biological Sciences | Treatments (e.g. chemicals, antibiotics) |
Related Links
Publications
l ‐3,4‐dihydroxyphenylalanine (l ‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parki
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1111/JNC.14676
Abstract: Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that l-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized motor performance, when excess Fe was present. Similarly, l-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.
Age modulates the injury-induced metallomic profile in the brain
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C6MT00260A
Abstract: The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents. The relative abundance of metals in corresponding regions within the ipsilateral and contralateral hemispheres as well as the hippoc us was assessed. Substantial region and time point specific alterations in Fe, Zn and Cu were identified immediately and up to 28 days post-TBI. The data from this follow-up study has also been compared to our previous data from young animals, and aged mice exhibit an appreciably enhanced and persistent elevation of all metals in every region surveyed, with in idual metal disparities at various time points observed post-injury. This may potentially contribute to the acceleration in the onset of cognitive decline and neurological disease that has been observed in the aged population following head trauma.
Acute Neurotoxicity Models of Prion Disease
Publisher: American Chemical Society (ACS)
Date: 02-02-2018
DOI: 10.1021/ACSCHEMNEURO.7B00517
Abstract: Prion diseases are phenotypically erse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrP
Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NBD.2015.03.015
Abstract: Iron accumulation and tau protein deposition are pathological features of Alzheimer's (AD) and Parkinson's diseases (PD). Soluble tau protein is lower in affected regions of these diseases, and we previously reported that tau knockout mice display motor and cognitive behavioral abnormities, brain atrophy, neuronal death in substantia nigra, and iron accumulation in the brain that all emerged between 6 and 12 months of age. This argues for a loss of tau function in AD and PD. We also showed that treatment with the moderate iron chelator, clioquinol (CQ) restored iron levels and prevented neuronal atrophy and attendant behavioral decline in 12-month old tau KO mice when commenced prior to the onset of deterioration (6 months). However, therapies for AD and PD will need to treat the disease once it is already manifest. So, in the current study, we tested whether CQ could also rescue the phenotype of mice with a developed phenotype. We found that 5-month treatment of symptomatic (13 months old) tau KO mice with CQ increased nigral tyrosine hydroxylase phosphorylation (which induces activity) and reversed the motor deficits. Treatment also reversed cognitive deficits and raised BDNF levels in the hippoc us, which was accompanied by attenuated brain atrophy, and reduced iron content in the brain. These data raise the possibility that lowering brain iron levels in symptomatic patients could reverse neuronal atrophy and improve brain function, possibly by elevating neurotrophins.
Lithium suppression of tau induces brain iron accumulation and neurodegeneration
Publisher: Springer Science and Business Media LLC
Date: 12-07-2016
DOI: 10.1038/MP.2016.96
Abstract: Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T
Tau protein: Relevance to Parkinson's disease
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.BIOCEL.2010.07.016
Abstract: Tau is a microtubule-associated protein linked with neurodegenerative diseases. Humans express six different isoforms of tau the longest containing four microtubule-binding repeat motifs in the C-terminal that are vital for what is considered the major biological function of tau, to stabilize microtubules and facilitate axonal transport. The capacity of tau to maintain its normal biological function is dependent upon its phosphorylation state. In Alzheimer's and Parkinson's diseases, there is a hyperphosphorylation of tau that leads to the intracellular accumulation of tau in the form of neurofibrillary tangles. While the role of tau in Parkinson's disease has been understated for some time, here we summarize key genetic, pathological and biochemical evidence supporting a role for tau in the pathogenesis of Parkinson's disease. Toxic interactions with alpha synuclein may lead to hyperphosphorylation of tau and eventually to the deposition of both proteins in the disease.
Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC02231B
Abstract: Studying the neuroanatomy of the mouse brain using imaging mass spectrometry and chemometric analysis.
Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
Publisher: Public Library of Science (PLoS)
Date: 04-2013
The effect of dopamine on MPTP-induced rotarod disability
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.NEULET.2013.02.066
Abstract: Dopamine depletion in Parkinson's disease (PD) results in bradykinesia and tremor. Therapeutic administration of the dopamine precursor, l-Dopa, alleviates these symptoms but dyskinesia's can manifest with chronic treatment. In the MPTP toxin mouse model of PD, lesion severity is often assessed by the rotarod behavioral assay. Dopamine depletion by MPTP is thought to induce rotarod behavioral decline. Here we surveyed rotarod behavior and striatal dopamine at timed intervals post-MPTP. Paradoxically, rotarod disability coincided with gradual striatal dopamine restoration. l-Dopa supplementation exacerbated rotarod disability, whereas dopamine antagonism restored performance. dopamine restoration, not depletion, precipitates rotarod disability after MPTP intoxication, and caution should be applied when using this assay for MPTP.
Search for Eccentric Binary Black Hole Mergers with Advanced LIGO and Advanced Virgo during Their First and Second Observing Runs
Publisher: American Astronomical Society
Date: 30-09-2019
Abstract: When formed through dynamical interactions, stellar-mass binary black holes (BBHs) may retain eccentric orbits ( e 0.1 at 10 Hz) detectable by ground-based gravitational-wave detectors. Eccentricity can therefore be used to differentiate dynamically formed binaries from isolated BBH mergers. Current template-based gravitational-wave searches do not use waveform models associated with eccentric orbits, rendering the search less efficient for eccentric binary systems. Here we present the results of a search for BBH mergers that inspiral in eccentric orbits using data from the first and second observing runs (O1 and O2) of Advanced LIGO and Advanced Virgo. We carried out the search with the coherent WaveBurst algorithm, which uses minimal assumptions on the signal morphology and does not rely on binary waveform templates. We show that it is sensitive to binary mergers with a detection range that is weakly dependent on eccentricity for all bound systems. Our search did not identify any new binary merger candidates. We interpret these results in light of eccentric binary formation models. We rule out formation channels with rates ≳100 Gpc −3 yr −1 for e 0.1, assuming a black hole mass spectrum with a power-law index ≲2.
Pramipexole restores depressed transmission in the ventral hippocampus following MPTP-lesion
Publisher: Springer Science and Business Media LLC
Date: 14-03-2017
DOI: 10.1038/SREP44426
Abstract: The hippoc us has a significant association with memory, cognition and emotions. The dopaminergic projections from both the ventral tegmental area and substantia nigra are thought to be involved in hippoc al activity. To date, however, few studies have investigated dopaminergic innervation in the hippoc us or the functional consequences of reduced dopamine in disease models. Further complicating this, the hippoc us exhibits anatomical and functional differentiation along its dorso-ventral axis. In this work we investigated the role of dopamine on hippoc al long term potentiation using D- hetamine, which stimulates dopamine release, and also examined how a dopaminergic lesion affects the synaptic transmission across the anatomic sub isions of the hippoc us. Our findings indicate that a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine induced dopaminergic lesion has time-dependent effects and impacts mainly on the ventral region of the hippoc us, consistent with the density of dopaminergic innervation. Treatment with a preferential D 3 receptor agonist pramipexole partly restored normal synaptic transmission and Long-Term Potentiation. These data suggest a new mechanism to explain some of the actions of pramipexole in Parkinson´s disease.
Isoflurane in the Aged Brain: A Link to Altered Amyloid Precursor Protein Processing
Publisher: Avens Publishing Group
Date: 2015
How Well Do Rodent Models of Parkinson’s Disease Recapitulate Early Non-Motor Phenotypes? A Systematic Review
Publisher: MDPI AG
Date: 24-11-2022
DOI: 10.3390/BIOMEDICINES10123026
Abstract: The prodromal phase of Parkinson’s disease (PD) is characterised by many non-motor symptoms, and these have recently been posited to be predictive of later diagnosis. Genetic rodent models can develop non-motor phenotypes, providing tools to identify mechanisms underlying the early development of PD. However, it is not yet clear how reproducible non-motor phenotypes are amongst genetic PD rodent models, whether phenotypes are age-dependent, and the translatability of these phenotypes has yet to be explored. A systematic literature search was conducted on studies using genetic PD rodent models to investigate non-motor phenotypes cognition, anxiety/depressive-like behaviour, gastrointestinal (GI) function, olfaction, circadian rhythm, cardiovascular and urinary function. In total, 51 genetic models of PD across 150 studies were identified. We found outcomes of most phenotypes were inconclusive due to inadequate studies, assessment at different ages, or variation in experimental and environmental factors. GI dysfunction was the most reproducible phenotype across all genetic rodent models. The mouse model harbouring mutant A53T, and the wild-type hα-syn overexpression (OE) model recapitulated the majority of phenotypes, albeit did not reliably produce concurrent motor deficits and nigral cell loss. Furthermore, animal models displayed different phenotypic profiles, reflecting the distinct genetic risk factors and heterogeneity of disease mechanisms. Currently, the inconsistent phenotypes within rodent models pose a challenge in the translatability and usefulness for further biomechanistic investigations. This review highlights opportunities to improve phenotype reproducibility with an emphasis on phenotypic assay choice and robust experimental design.
Prion acute synaptotoxicity is largely driven by protease-resistant PrPSc species
Publisher: Public Library of Science (PLoS)
Date: 08-08-2018
GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein
Publisher: Springer Science and Business Media LLC
Date: 14-11-2014
DOI: 10.1038/CDD.2014.179
Analysis of morphological and neurochemical changes in subthalamic nucleus neurons in response to a unilateral 6-OHDA lesion of the substantia nigra in adult rats
Publisher: Elsevier BV
Date: 06-2021
Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C2MT20164J
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent toxin used to selectively destroy dopaminergic neurons in the substantia nigra and induce parkinsonism. MPTP is metabolised to the 1-methyl-4-phenylpyridinium ion (MPP(+)) in glia, after which it enters the neuron via the dopamine transporter and results in elevated levels of oxidative stress. The mechanism through which MPP(+) causes cell death is thought to involve redox-active metals, particularly iron (Fe). This review will examine how cellular metal metabolism is altered following MPTP insult, and how this relates to metal dyshomeostasis in idiopathic Parkinson's disease. This includes both cell damage arising from increased metal concentration, and how metal-binding proteins respond to MPTP-induced neurotoxicity. Implications for using MPTP as a model for human Parkinson's disease will be discussed in terms of cell metallobiology.
Biomaterial Strategies for Restorative Therapies in Parkinson's Disease
Publisher: American Chemical Society (ACS)
Date: 11-10-2021
Migration and Differentiation of Neural Stem Cells Diverted From the Subventricular Zone by an Injectable Self-Assembling β-Peptide Hydrogel
Publisher: Frontiers Media SA
Date: 08-11-2019
Type-1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson's disease
Publisher: Wiley
Date: 12-07-2016
DOI: 10.1002/GLIA.23028
Abstract: Type-1 interferons (IFNs) are pleiotropic cytokines with a critical role in the initiation and regulation of the pro-inflammatory response. However, the contribution of the type-1 IFNs to CNS disorders, specifically chronic neuropathologies such as Parkinson's disease is still unknown. Here, we report increased type-1 IFN signaling in both post mortem human Parkinson's disease s les and in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model. In response to MPTP, mice lacking the type-1 IFN receptor (IFNAR1(-/-) ) displayed decreased type-1 IFN signaling, an attenuated pro-inflammatory response and reduced loss of dopaminergic neurons. The neuroprotective potential of targeting the type-1 IFN pathway was confirmed by reduced neuroinflammation and DA cell death in mice treated with a blocking monoclonal IFNAR1 (MAR-1) antibody. The MPTP/MAR-1 treated mice also displayed increased striatal dopamine levels and improved behavioural outcomes compared to their MPTP/IgG controls. These data, implicate for the first time, a deleterious role for the type-1 IFNs as key modulators of the early neuroinflammatory response and therefore the neuronal cell death in Parkinson's disease. GLIA 2016 :1590-1604.
Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities
Publisher: Oxford University Press (OUP)
Date: 02-08-2008
DOI: 10.1093/HMG/DDN224
Abstract: Enlarged early endosomes in the neurons of young Down syndrome (DS) and pre-Alzheimer's disease (AD) brains suggest that a disturbance in endocytosis is one of the earliest hallmarks of AD pathogenesis in both conditions. We identified a chromosome 21 gene, Intersectin-1 (ITSN1) that is up-regulated in DS brains and has a putative function in endocytosis and vesicle trafficking. To elucidate the function of ITSN1 and assess its contribution to endocytic defects associated with DS and AD, we generated Itsn1 null mice. In knockout mice we found alterations in a number of parameters associated with endocytic and vesicle trafficking events. We found a reduced number of exocytosis events in chromaffin cells and a slowing of endocytosis in neurons. Endosome size was increased in neurons and NGF levels were reduced in the septal region of the brain. Our data is the first indication that Itsn1 has a role in endocytosis in an in vivo mammalian model, and that a disruption in Itsn1 expression causes a disturbance in vesicle trafficking and endocytic function in the brain. These results imply a role for ITSN1 in the early endocytic anomalies reported in DS brains which may have ramifications for the onset of AD.
Interactions of metals and Apolipoprotein E in Alzheimer’s disease
Publisher: Frontiers Media SA
Date: 12-06-2014
Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export
Publisher: Springer Science and Business Media LLC
Date: 29-01-2012
DOI: 10.1038/NM.2613
Abstract: The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.
Distribution of Parkinson's disease associated RAB39B in mouse brain tissue
Publisher: Springer Science and Business Media LLC
Date: 30-03-2020
DOI: 10.1186/S13041-020-00584-7
Abstract: Pathogenic variants in the gene encoding the small GTPase Ras analogue in Brain 39b (RAB39B) are associated with early-onset parkinsonism. In this study we investigated the expression and localization of RAB39B (RNA and protein) in mouse brain tissue to gain a better understanding of its normal physiological function(s) and role in disease. We developed novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, and performed real-time PCR and western blot analysis on whole brain lysates. To determine the spatial localization of Rab39b RNA and protein, we performed in-situ hybridization and immunohistochemistry on fresh frozen and fixed brain tissue. Our results show that RAB39B is localized throughout the cortex, hippoc us and substantia nigra of mice throughout postnatal life. We found high levels of RAB39B within MAP2 positive cortical and hippoc al neurons, and TH positive dopaminergic neurons in the substantia nigra pars compacta . Our studies support and extend current knowledge of the localization of RAB39B. We validate RAB39B as a neuron-enriched protein and demonstrate that it is present throughout the mouse cortex and hippoc us. Further, we observe high levels in the substantia nigra pars compacta , the brain region most affected in Parkinson’s disease pathology. The distribution of Rab39b is consistent with human disease associations with parkinsonism and cognitive impairment. We also describe and validate novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, both of which are valuable tools for future studies of the molecular function of RAB39B.
Comparative Study of Metal Quantification in Neurological Tissue Using Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry Imaging and X-ray Fluorescence Microscopy
Publisher: American Chemical Society (ACS)
Date: 09-06-2015
DOI: 10.1021/ACS.ANALCHEM.5B01454
Abstract: Redox-active metals in the brain mediate numerous biochemical processes and are also implicated in a number of neurodegenerative diseases. A number of different approaches are available for quantitatively measuring the spatial distribution of biometals at an image resolution approaching the subcellular level. Measured biometal levels obtained using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS spatial resolution 15 μm × 15 μm) were within the range of those obtained using X-ray fluorescence microscopy (XFM spatial resolution 2 μm × 7 μm) and regional changes in metal concentration across discrete brain regions were replicated to the same degree. Both techniques are well suited to profiling changes in regional biometal distribution between healthy and diseased brain tissues, but absolute quantitation of metal levels varied significantly between methods, depending on the metal of interest. Where all possible variables affect metal levels, independent of a treatment henotype are controlled, either method is suitable for examining differences between experimental groups, though, as with any method for imaging post mortem brain tissue, care should be taken when interpreting the total metal levels with regard to physiological concentrations.
Neurite infiltration and cellular response to electrospun polycaprolactone scaffolds implanted into the brain
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.BIOMATERIALS.2009.05.011
Abstract: Assessment of axonal infiltration and guidance within neural tissue engineering scaffolds, along with the characterisation of the inflammatory response, is critical in determining these scaffolds' potential for facilitating neural repair. In this study, the extent of microglial and astrocytic response was measured following implantation of electrospun poly(epsilon-caprolactone) (PCL) scaffolds into the caudate putamen of the adult rat brain. The inflammation peaked at around 4 days (microglia) and 7 days (astrocytes) and subsided to homeostatic levels by 60 days. There was no evidence of microglial encapsulation and indeed neurites had infiltrated the implants, evidence of scaffold-neural integration. Whilst the inflammatory response was uninfluenced by the degree of PCL fibre alignment, the extent of neurite entry was. Large porosity, as was the case with the randomly orientated polymer fibres, enabled neurite infiltration and growth within the scaffold. However, neuronal processes could not penetrate scaffolds when fibres were partially aligned and instead, preferentially grew perpendicular to the direction of PCL fibre alignment at the implant-tissue interface i.e. perpendicular, not parallel, contact guidance was provided. This investigation shows that electrospun PCL fibres are compatible with brain tissue and provide preliminary insights regarding the influence of microglia and astrocytes in neural integration within such scaffolds.
The Long Isoform of Intersectin-1 Has a Role in Learning and Memory
Publisher: Frontiers Media SA
Date: 25-02-2020
The role of lipids in α-synuclein misfolding and neurotoxicity
Publisher: Elsevier BV
Date: 06-2019
Enhancing neurite outgrowth from primary neurones and neural stem cells using thermoresponsive hydrogel scaffolds for the repair of spinal cord injury
Publisher: Wiley
Date: 10-04-2009
DOI: 10.1002/JBM.A.31962
Abstract: In this study, thermoresponsive xyloglucan hydrogel scaffolds were investigated as candidates for neural tissue engineering of the spinal cord. The hydrogels were optimized to provide similar mechanical properties to that of native spinal cord, although also being functionalized through the immobilization of poly-D-lysine to promote neurone adhesion and neurite outgrowth. Under 2D and 3D culture conditions, xyloglucan scaffolds supported the differentiation of primary cortical neurones. Furthermore, functionalization provided a means of controlling and optimizing the cell diameter, number, migration and the neurite density, and the direction of growth. The interaction of neural stem cells (NSCs) was also investigated on the xyloglucan scaffolds in vitro. The survival of the NSCs and the axonal extensions on the scaffolds were similar to that of the primary cortical neurones. These findings suggest that xyloglucan-based materials are suitable for providing a neurotrophic milieu.
Increased Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels.
Publisher: Public Library of Science (PLoS)
Date: 24-01-2014
Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1039/C8MT00068A
Abstract: Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age.
Ferroptosis and cell death mechanisms in Parkinson's disease
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NEUINT.2017.01.004
Abstract: Symptoms of Parkinson's disease arise due to neuronal loss in multiple brain regions, especially dopaminergic neurons in the substantia nigra pars compacta. Current therapies aim to restore dopamine levels in the brain, but while these provide symptomatic benefit, they do not prevent ongoing neurodegeneration. Preventing neuronal death is a major strategy for disease-modifying therapies however, while many pathogenic factors have been identified, it is currently unknown how neurons die in the disease. Ferroptosis, a recently identified iron-dependent cell death pathway, involves several molecular events that have previously been implicated in PD. This review will discuss ferroptosis and other cell death pathways implicated in PD neurodegeneration, with a focus on the potential to therapeutically target these pathways to slow the progression of this disease.
Is early-life iron exposure critical in neurodegeneration?
Publisher: Springer Science and Business Media LLC
Date: 23-06-2015
DOI: 10.1038/NRNEUROL.2015.100
Abstract: The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and lifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements.
Implantation of Functionalized Thermally Gelling Xyloglucan Hydrogel Within the Brain: Associated Neurite Infiltration and Inflammatory Response
Publisher: Mary Ann Liebert Inc
Date: 09-2010
Excessive early-life dietary exposure: a potential source of elevated brain iron and a risk factor for Parkinson’s disease
Publisher: Springer Science and Business Media LLC
Date: 05-01-2017
DOI: 10.1038/S41531-016-0004-Y
Abstract: Iron accumulates gradually in the ageing brain. In Parkinson’s disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that in iduals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson’s diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children (b) translate this biomarker to adults (c) integrate it with in vivo brain iron in Parkinson’s disease and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson’s disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson’s diseases and produce a potential biomarker of Parkinson’s disease risk in preclinical in iduals.
In vivo prion models and the disconnection between transmissibility and neurotoxicity
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.ARR.2017.03.007
Abstract: The primary causative event in the development of prion diseases is the misfolding of the normal prion protein (PrP
Targeting metals rescues the phenotype in an animal model of tauopathy
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1039/C8MT00153G
Abstract: Targeting metals improves the behavioural, anatomical and biochemical phenotype present in a mouse model of tauopathy.
Effects of Excess Iron on the Retina: Insights From Clinical Cases and Animal Models of Iron Disorders
Publisher: Frontiers Media SA
Date: 03-02-2022
DOI: 10.3389/FNINS.2021.794809
Abstract: Iron plays an important role in a wide range of metabolic pathways that are important for neuronal health. Excessive levels of iron, however, can promote toxicity and cell death. An ex le of an iron overload disorder is hemochromatosis (HH) which is a genetic disorder of iron metabolism in which the body’s ability to regulate iron absorption is altered, resulting in iron build-up and injury in several organs. The retina was traditionally assumed to be protected from high levels of systemic iron overload by the blood-retina barrier. However, recent data shows that expression of genes that are associated with HH can disrupt retinal iron metabolism. Thus, the effects of iron overload on the retina have become an area of research interest, as excessively high levels of iron are implicated in several retinal disorders, most notably age–related macular degeneration. This review is an effort to highlight risk factors for excessive levels of systemic iron build-up in the retina and its potential impact on the eye health. Information is integrated across clinical and preclinical animal studies to provide insights into the effects of systemic iron loading on the retina.
Pathogenic mechanisms of prion protein, amyloid‐β and α‐synuclein misfolding: the prion concept and neurotoxicity of protein oligomers
Publisher: Wiley
Date: 15-09-2016
DOI: 10.1111/JNC.13772
Abstract: Proteinopathies represent a group of diseases characterized by the unregulated misfolding and aggregation of proteins. Accumulation of misfolded protein in the central nervous system (CNS) is associated with neurodegenerative diseases, such as the transmissible spongiform encephalopathies (or prion diseases), Alzheimer's disease, and the synucleinopathies (the most common of which is Parkinson's disease). Of these, the pathogenic mechanisms of prion diseases are particularly striking where the transmissible, causative agent of disease is the prion, or proteinaceous infectious particle. Prions are composed almost exclusively of PrP
Investigation of nerve pathways mediating colorectal dysfunction in Parkinson’s disease model produced by lesion of nigrostriatal dopaminergic neurons
Publisher: Wiley
Date: 08-06-2020
DOI: 10.1111/NMO.13893
Therapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina
Publisher: Wiley
Date: 09-07-2020
DOI: 10.1002/JNR.24685
Cell infiltration into a 3D electrospun fiber and hydrogel hybrid scaffold implanted in the brain
Publisher: Informa UK Limited
Date: 2015
Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau
Publisher: Springer Science and Business Media LLC
Date: 11-08-2015
Fibrillar α-synuclein toxicity depends on functional lysosomes
Publisher: Elsevier BV
Date: 12-2020
Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data
Publisher: American Astronomical Society
Date: 26-06-2019
Implantable amyloid hydrogels for promoting stem cell differentiation to neurons
Publisher: Springer Science and Business Media LLC
Date: 09-2016
DOI: 10.1038/AM.2016.116
Neural Tissue Engineering of the CNS Using Hydrogels - A review (vol 5, pg 293, 2003)
Publisher: Wiley
Date: 13-10-2009
DOI: 10.1002/JBM.B.31207
Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.NEUROSCIENCE.2008.07.029
Abstract: Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8 also classified as relaxin family peptide 2 receptor RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus. High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial habenula. Lgr8 transcripts were also detected in frontal and motor cortices. The comparative distribution of LGR8 (receptor protein) was examined by autoradiography of [125I]-human INSL3 binding sites, with high densities detected in the thalamus, especially in Pf, and in the entire striatum--the caudate putamen (CPmicro), islands of Calleja, olfactory tubercle, nucleus accumbens--with lower levels in distinct layers of cerebral cortex. Notably, these areas also receive dopaminergic projections. These findings demonstrate the existence of LGR8 in neuronal soma in the thalamus and axons/terminals in thalamic target areas such as the striatum and frontal cortex. LGR8 was also detected throughout the medial habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites. These findings suggest the existence of a broadly distributed LGR8 signaling system in the rat involved in sensorimotor, limbic and cognitive functions. Further studies are now required to elucidate the precise function of LGR8, under normal and pathological conditions, as importantly, several of the equivalent receptor-positive areas in human brain are part of the pathology of neurodegenerative conditions including Parkinson's disease.
Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice
Publisher: American Chemical Society (ACS)
Date: 30-10-2016
DOI: 10.1021/ACSCHEMNEURO.5B00253
Abstract: The abnormal accumulation of alpha-synuclein (α-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinson's disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human α-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and α-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble α-syn aggregates, α-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippoc al and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/α-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies.
Erratum: “Searches for Gravitational Waves from Known Pulsars at Two Harmonics in 2015–2017 LIGO Data” (2019, ApJ, 879, 10)
Publisher: American Astronomical Society
Date: 26-08-2020
A time-course analysis of changes in cerebral metal levels following a controlled cortical impact
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C5MT00234F
Abstract: A LA-ICP-MS time course study of changing metal concentrations following traumatic brain injury in mice.
Metal chaperones prevent zinc-mediated cognitive decline
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NBD.2014.12.012
Abstract: Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95 AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippoc us. While we demonstrated a small regional increase in hippoc al zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippoc al formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.
All-sky search for continuous gravitational waves from isolated neutron stars using Advanced LIGO O2 data
Publisher: American Physical Society (APS)
Date: 08-10-2024
Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics
Publisher: MDPI AG
Date: 21-01-2022
DOI: 10.3390/JPM12020144
Abstract: Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.
Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain
Publisher: Public Library of Science (PLoS)
Date: 15-03-2016
N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington’s disease
Publisher: Oxford University Press (OUP)
Date: 14-05-2016
DOI: 10.1093/HMG/DDW144
Abstract: Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system x
Metals in Alzheimer's and Parkinson's Disease: Relevance to Dementia with Lewy Bodies
Publisher: Springer Science and Business Media LLC
Date: 08-08-2016
DOI: 10.1007/S12031-016-0809-5
Abstract: Despite being a common form of dementia, dementia with Lewy bodies is relatively under-researched when compared with Parkinson's disease and Alzheimer's disease. This has arisen from the fact that dementia with Lewy bodies has been historically difficult to diagnose resulting in a lack of well-defined clinical cohorts and post-mortem tissue available for scientific research. Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease so it is therefore likely that it also has similar pathogenic mechanisms leading to disease. This review will discuss the role of biological metals in Parkinson's disease and Alzheimer's disease and whether there are indications that metals may also be involved in dementia with Lewy bodies.
An iron–dopamine index predicts risk of parkinsonian neurodegeneration in the substantia nigra pars compacta
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3SC53461H
Abstract: Imaging of iron and dopamine by laser ablation-inductively coupled plasma-mass spectrometry reveals a risk index for parkinsonian neurodegeneration
Improving acquisition times of elemental bio-imaging for quadrupole-based LA-ICP-MS
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1JA10301F
Review Paper: A Review of the Cellular Response on Electrospun Nanofibers for Tissue Engineering
Publisher: SAGE Publications
Date: 12-12-2009
Abstract: Electrospinning has been employed extensively in tissue engineering to generate nanofibrous scaffolds from either natural or synthetic biodegradable polymers to simulate the cellular microenvironment. Electrospinning rapidly produces fibers of the nanolength scale and the process offers many opportunities to tailor the physical, chemical, and biological properties of a material for specific applications and cellular environments. There is growing evidence that nanofibers lify certain biological responses such as contact guidance and differentiation, however this has not been fully exploited in tissue engineering. This review addresses the cellular interactions with electrospun scaffolds, with particular focus on neural, bone, cartilage, and vascular tissue regeneration. Some aspects of scaffold design, including architectural properties, surface functionalization and materials selection are also addressed.
Trehalose improves traumatic brain injury-induced cognitive decline
Publisher: Public Library of Science (PLoS)
Date: 24-08-2017
Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.NBD.2021.105509
Abstract: Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.
Transferrin protects against Parkinsonian neurotoxicity and is deficient in Parkinson’s substantia nigra
Publisher: Springer Science and Business Media LLC
Date: 02-09-2016
Abstract: Iron deposition in Parkinson’s disease (PD) is a potential disease-modifying target. We previously showed that supplementation of the iron-exporter, ceruloplasmin, selectively corrected nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Ceruloplasmin delivers iron to transferrin (Tf), the extracellular iron-transporting protein. We show that Tf protein levels are decreased in the nigra of post-mortem PD brains compared with controls (−35% n =10 each). Because Tf traffics iron away from iron-replete tissues, we hypothesized that Tf supplementation could selectively facilitate iron export from the nigra in PD. In cultured neurons, Tf treatment corrected iron accumulation, and subcutaneous Tf to mice ameliorated iron accumulation and motor deficits in the MPTP model of PD. Although these data support a role for Tf in the disease mechanism for PD, and its potential use for correcting disorders of iron overload, Tf therapy also caused systemic iron depletion, which could limit its application for PD.
Zinc affects the proteolytic stability of Apolipoprotein E in an isoform-dependent way
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NBD.2015.06.016
Abstract: The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset rogression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma s les from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD.
Role of metal ions in the cognitive decline of Down syndrome
Publisher: Frontiers Media SA
Date: 23-06-2014
Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson’s disease
Publisher: Wiley
Date: 10-11-2019
DOI: 10.1111/NMO.13755
Abstract: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non‐motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α‐synuclein distribution. Chronic isolation stress was induced by single‐housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group‐housed. Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole‐gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment‐induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single‐housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha‐synuclein (αsyn) in myenteric ganglia under both housing conditions. Chronic isolation stress exacerbates PD‐associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation.
Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse
Publisher: American Chemical Society (ACS)
Date: 07-01-2016
DOI: 10.1021/ACSCHEMNEURO.5B00305
Abstract: Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using clioquinol later in life.
Glia and zinc in ageing and Alzheimer's disease: a mechanism for cognitive decline?
Publisher: Frontiers Media SA
Date: 25-06-2014
PrPSc Oligomerization Appears Dynamic, Quickly Engendering Inherent M1000 Acute Synaptotoxicity.
Publisher: Elsevier BV
Date: 07-2020
Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
Correction to: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease (Acta Neuropathologica Communications, (2017), 5, 1, (53), 10.1186/s40478-017-0456-2)
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
Exercise and physical activity for people with Progressive Supranuclear Palsy: a systematic review
Publisher: SAGE Publications
Date: 27-09-2019
Abstract: To conduct a systematic review to evaluate exercise and structured physical activity for people living with Progressive Supranuclear Palsy. AMED, CINAHL, Cochrane, EMBASE, Informit, MEDLINE, PEDro, PsycINFO, PubMed and SportDiscus were searched until 18 August 2019. Reference lists of included studies were hand-searched. Cochrane guidelines informed review methods. English language peer-reviewed studies of any design, in any setting, were included. Method quality was appraised with the Physiotherapy Evidence Database scale and Joanna Briggs Institute instruments. Data were extracted for study design, s le characteristics and therapy content. Effectiveness was calculated where possible. Eleven studies were included. Method appraisal showed moderate to high risk of bias. Research designs included three randomized controlled trials, two quasi-experimental studies, one cohort study, four case studies and one case series. S le sizes ranged from 1 to 24. Exercise interventions included supported and robot-assisted gait training, gaze training, balance re-education and auditory-cued motor training. Dosage ranged from two to five sessions per week over four to eight weeks. End-of-intervention effect sizes were small (6-minute walk test: –0.07 95% confidence interval (CI): –0.87, 0.73) to moderate (balance: –0.61 95% CI: –1.40, 0.23 Timed Up and Go: 0.42 95% CI: –0.49, 1.33) and statistically non-significant. Function, quality of life and adverse events were inconsistently reported. For people with Progressive Supranuclear Palsy, robust evidence was not found for therapeutic exercises. Reported improvements in walking were derived from two clinical trials. The effects of structured physical activity for people with advanced Progressive Supranuclear Palsy are not known.
An intact membrane is essential for small extracellular vesicle‐induced modulation of α‐synuclein fibrillization
Publisher: Wiley
Date: 12-2020
DOI: 10.1002/JEV2.12034
Metal chaperones: a novel therapeutic strategy for brain injury?
Publisher: Informa UK Limited
Date: 03-12-2018
DOI: 10.1080/02699052.2018.1552988
Abstract: This study sought to assess the potential efficacy of a novel class of metal chaperone on the outcomes in an animal model of a controlled cortical impact. This work was predicated on previous observations that this class of compound has exhibited neuroprotective potential in other models of aging and neurodegeneration. The study employed a controlled cortical impact traumatic brain injury in three month old mice with subsequent behavioral and cellular assessments to determine therapeutic efficacy. Cognitive (Y-maze) and motor assessments (Rotarod and Open Field) were employed to determine behavioral end points. Histological-based methods were utilized to assess neuronal integrity, astrocytosis, and lesion volume. We demonstrate here that acute post-injury treatment with PBT2 (Prana Biotechnology) is sufficient to maintain neuronal integrity (evidenced by decreased lesion area and increased numbers of neurons decreased astrocytosis was also present) and to normalize performance in cognitive testing (Y-maze). These effects occurred within days and were maintained for the entire duration of the study (26 days post-injury). These data support the further interrogation of the utility of metal chaperones for the treatment and/or prevention of the neuroanatomical, biochemical, and behavioral deficits that occur following brain injuries of different etiologies.
The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease
Publisher: Springer Science and Business Media LLC
Date: 28-06-2017
DOI: 10.1186/S40478-017-0456-2
Abstract: Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology . In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.
The association of enteric neuropathy with gut phenotypes in acute and progressive models of Parkinson’s disease
Publisher: Springer Science and Business Media LLC
Date: 12-04-2021
DOI: 10.1038/S41598-021-86917-5
Abstract: Parkinson’s disease (PD) is associated with neuronal damage in the brain and gut. This work compares changes in the enteric nervous system (ENS) of commonly used mouse models of PD that exhibit central neuropathy and a gut phenotype. Enteric neuropathy was assessed in five mouse models: peripheral injection of MPTP intracerebral injection of 6-OHDA oral rotenone and mice transgenic for A53T variant human α-synuclein with and without rotenone. Changes in the ENS of the colon were quantified using pan-neuronal marker, Hu, and neuronal nitric oxide synthase (nNOS) and were correlated with GI function. MPTP had no effect on the number of Hu+ neurons but was associated with an increase in Hu+ nuclear translocation (P 0.04). 6-OHDA lesioned mice had significantly fewer Hu+ neurons/ganglion (P 0.02) and a reduced proportion of nNOS+ neurons in colon (P 0.001). A53T mice had significantly fewer Hu+ neurons/area (P 0.001) and exhibited larger soma size (P 0.03). Treatment with rotenone reduced the number of Hu+ cells/mm 2 in WT mice (P 0.006) and increased the proportion of Hu+ translocated cells in both WT (P 0.02) and A53T mice (P 0.04). All PD models exhibited a degree of enteric neuropathy, the extent and type of damage to the ENS, however, was dependent on the model.
Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease
Publisher: Wiley
Date: 19-02-2013
DOI: 10.1002/ANA.23817
Abstract: Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD.
Optically targeted search for gravitational waves emitted by core-collapse supernovae during the first and second observing runs of advanced LIGO and advanced Virgo
Publisher: American Physical Society (APS)
Date: 02-04-2020
Rescue of the Friedreich Ataxia Knockout Mutation in Transgenic Mice Containing an FXN-EGFP Genomic Reporter
Publisher: Public Library of Science (PLoS)
Date: 25-03-2014
α-Synuclein Transgenic Mice Reveal Compensatory Increases in Parkinson's Disease-Associated Proteins DJ-1 and Parkin and Have Enhanced α-Synuclein and PINK1 Levels After Rotenone Treatment
Publisher: Springer Science and Business Media LLC
Date: 13-05-2010
DOI: 10.1007/S12031-010-9378-1
Abstract: Parkinson's disease (PD) is a severe neurodegenerative disorder characterised by loss of dopaminergic neurons of the substantia nigra. The pathological hallmarks are cytoplasmic inclusions termed Lewy bodies consisting primarily of aggregated alpha-synuclein (alphaSN). Different lines of transgenic mice have been developed to model PD but have failed to recapitulate the hallmarks of this disease. Since treatment of rodents with the pesticide rotenone can reproduce nigrostriatal cell loss and other features of PD, we aimed to test chronic oral administration of rotenone to transgenic mice over-expressing human alphaSN with the A53T mutation. Initial assessment of this transgenic line for compensatory molecular changes indicated decreased brain beta-synuclein expression and significantly increased levels of the PD-associated oxidative stress response protein, DJ-1, and the E3 ubiquitin ligase enzyme, Parkin. Rotenone treatment of 30 mg/kg for 25 doses over a 35-day period was tolerated in the transgenic mice and resulted in decreased spontaneous locomotor movement and increased cytoplasmic alphaSN expression. The mitochondrial Parkinson's-associated PTEN-induced kinase 1 protein levels were also increased in transgenic mouse brain after rotenone treatment there was no change in brain dopamine levels or nigrostriatal cell loss. These hA53T alphaSN transgenic mice provide a useful model for presymptomatic Parkinson's features and are valuable for study of associated compensatory changes in early Parkinson's disease stages.
Regional iron distribution and soluble ferroprotein profiles in the healthy human brain
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.PNEUROBIO.2019.101744
Abstract: Iron is essential for brain development and health where its redox properties are used for a number of neurological processes. However, iron is also a major driver of oxidative stress if not properly controlled. Brain iron distribution is highly compartmentalised and regulated by a number of proteins and small biomolecules. Here, we examine heterogeneity in regional iron levels in 10 anatomical structures from seven post-mortem human brains with no apparent neuropathology. Putamen contained the highest levels, and most case-to-case variability, of iron compared with the other regions examined. Partitioning of iron between cytosolic and membrane-bound iron was generally consistent in each region, with a slightly higher proportion (55 %) in the 'insoluble' phase. We expand on this using the Allen Human Brain Atlas to examine patterns between iron levels and transcriptomic expression of iron regulatory proteins and using quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry to assess regional differences in the molecular masses to which cytosolic iron predominantly binds. Approximately 60 % was associated with ferritin, equating to approximately 25 % of total tissue iron essentially in storage. This study is the first of its kind in human brain tissue, providing a valuable resource and new insight for iron biologists and neuroscientists, alike.
Analogues of desferrioxamine B designed to attenuate iron-mediated neurodegeneration: synthesis, characterisation and activity in the MPTP-mouse model of Parkinson's disease
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C7MT00039A
Abstract: One dual-function ( 2 ) and one first-generation ( 9 ) conjugate of the Fe( iii ) chelator desferrioxamine B (DFOB, 1 ) showed significant rescue of neurons in the MPTP mouse model of Parkinson's disease.
All-sky search for short gravitational-wave bursts in the second Advanced LIGO and Advanced Virgo run
Publisher: American Physical Society (APS)
Date: 11-07-2019
Surface and bulk characterisation of electrospun membranes: Problems and improvements
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.COLSURFB.2009.01.022
Abstract: Electrospun membranes are used in a variety of applications, including filtration systems and sensors for chemical detection, and have attracted increased interest in the field of tissue engineering and regenerative medicine. Successful integration of these materials into a specific technology will require understanding of the fibres' surface, bulk and architectural properties. Detailed characterisation of these properties is frequently overlooked, particularly in specialised interdisciplinary fields such as tissue engineering. In this article we have reviewed the current status of the characterisation of electrospun membranes, while recommending improvements in using these techniques to better understand these very interesting nanostructured materials.
α-Synuclein Regulates Development and Function of Cholinergic Enteric Neurons in the Mouse Colon.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.NEUROSCIENCE.2019.10.029
Abstract: Alpha-Synuclein (α-Syn) is expressed in the central nervous system and the nervous system of the gut (enteric nervous system, ENS), and is well known to be the major constituent of Lewy bodies which are the hallmark of Parkinson's disease. Gastrointestinal disorders frequently manifest several years before motor deficits develop in Parkinson's patients. Despite extensive research on pathological rodent models, the physiological role of α-Syn in the normal ENS is unclear h ering analysis of its neuropathology. We compared the ENS in colons of α-Syn-knockout (α-Syn KO) and wild-type mice using immunohistochemistry and calcium-imaging of responses to synaptic input. We found that α-Syn is predominantly expressed in cholinergic varicosities, which contain vesicular acetylcholine transporter. α-Syn KO mice had higher enteric neuron density and a larger proportion of cholinergic neurons, notably those containing calretinin, demonstrating a role for α-Syn in regulating development of these neurons. Moreover, α-Syn deletion enhanced the litude of synaptically activated [Ca
Parkinson's Disease Iron Deposition Caused by Nitric Oxide-Induced Loss of β-Amyloid Precursor Protein
Publisher: Society for Neuroscience
Date: 25-02-2015
DOI: 10.1523/JNEUROSCI.3439-14.2015
Abstract: Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated β-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP −/− mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
A novel approach to rapidly prevent age-related cognitive decline
Publisher: Wiley
Date: 04-12-2014
DOI: 10.1111/ACEL.12178
Restoration of intestinal function in an MPTP model of Parkinson’s Disease
Publisher: Springer Science and Business Media LLC
Date: 29-07-2016
DOI: 10.1038/SREP30269
Abstract: Patients with Parkinson’s disease often experience non-motor symptoms including constipation, which manifest prior to the onset of debilitating motor signs. Understanding the causes of these non-motor deficits and developing disease modifying therapeutic strategies has the potential to prevent disease progression. Specific neuronal subpopulations were reduced within the myenteric plexus of mice 21 days after intoxication by the intraperitoneal administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and was associated with a reduction in stool frequency, indicative of intestinal dysfunction. Oral administration of the alent copper complex, Cu II (atsm), which has been shown to be neuroprotective and restore motor performance to MPTP lesioned mice, improved stool frequency and was correlated with restoration of neuronal subpopulations in the myenteric plexus of MPTP lesioned mice. Restoration of intestinal function was associated with reduced enteric glial cell reactivity and reduction of markers of inflammation. Therapeutics that have been shown to be neuroprotective in the central nervous system, such as Cu II (atsm), therefore also provide symptom relief and are disease modifying in the intestinal tract, suggesting that there is a common cause of Parkinson’s disease pathogenesis in the enteric nervous system and central nervous system.
Cognitive loss in zinc transporter-3 knock-out mice: A phenocopy for the synaptic and memory deficits of Alzheimer's disease?
Publisher: Society for Neuroscience
Date: 03-02-2010
DOI: 10.1523/JNEUROSCI.5255-09.2010
Abstract: Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn 2+ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippoc al proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (−46% p 0.01) the postsynaptic protein PSD95 (−37% p 0.01) the glutamate receptors AMPAR (−34% p 0.01), NMDAR2a (−64% p 0.001), and NMDAR2b (−49% p 0.05) the surrogate marker of neurogenesis doublecortin (−31% p 0.001) and elements of the BDNF pathway, pro-BDNF (−30% p 0.05) and TrkB (−22% p 0.01). In addition, there is a concomitant decrease in neuronal spine density (−6% p 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (−50% p 0.01) in healthy older humans (ages, 48–91 years r 2 = 0.47 p = 0.00019) and particularly in Alzheimer's disease (AD) (−36% p 0.0001). Thus, age-dependent loss of transsynaptic Zn 2+ movement leads to cognitive loss, and since extracellular β-amyloid is aggregated by and traps this pool of Zn 2+ , the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.
Reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism
Publisher: Springer Science and Business Media LLC
Date: 23-10-2020
DOI: 10.1038/S41598-020-74495-X
Abstract: Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson’s disease (PD) (n = 20) participants underwent 18 F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. 18 F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson’s Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.
Misfolded alpha-synuclein causes hyperactive respiration without functional deficit in live neuroblastoma cells
Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/DMM.040899
Abstract: The misfolding and aggregation of the largely disordered protein, α-synuclein, is a central pathogenic event that occurs in the synucleinopathies a group of neurodegenerative disorders that includes Parkinson's disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated α-synuclein are unresolved. Here, we studied the pathogenicity of misfolded α-synuclein produced using the Protein Misfolding Cyclic Amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded α-synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded α-synuclein. To investigate if such an interaction can impact the properties of α-synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show CA both accelerates the rate of α-synuclein fibrillization and produces species that harbour enhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live non-transgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed misfolded α-synuclein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong support for the mitochondrion as a target for misfolded α-synuclein and reveals persistent, hyperactive respiration as a potential up-stream pathogenic event associated with the synucleinopathies.
Three-dimensional elemental bio-imaging of Fe, Zn, Cu, Mn and P in a 6-hydroxydopamine lesioned mouse brain
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1039/C0MT00039F
Abstract: Three dimensional maps of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and phosphorous (P) in a 6-hydroxydopamine (6-OHDA) lesioned mouse brain were constructed employing a novel quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method known as elemental bio-imaging. The 3D maps were produced by ablating serial consecutive sections taken from the same animal. Each section was quantified against tissue standards resulting in a three dimensional map that represents the variation of trace element concentrations of the mouse brain in the area surrounding the substantia nigra (SN). Damage caused by the needle or the toxin did not alter the distribution of Zn, and Cu but significantly altered Fe in and around the SN and both Mn and Fe around the needle track. A 20% increase in nigral Fe concentration was observed within the lesioned hemisphere. This technique clearly shows the natural heterogeneous distributions of these elements throughout the brain and the perturbations that occur following trauma or intoxication. The method may applied to three-dimensional modelling of trace elements in a wide range of tissue s les.
Motor and cognitive deficits in aged tau knockout mice in two background strains
Publisher: Springer Science and Business Media LLC
Date: 14-08-2014
Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc
Publisher: Public Library of Science (PLoS)
Date: 10-04-2019
Clinical Sphingolipids Pathway in Parkinson’s Disease: From GCase to Integrated-Biomarker Discovery
Publisher: MDPI AG
Date: 15-04-2022
Abstract: Alterations in the sphingolipid metabolism of Parkinson’s Disease (PD) could be a potential diagnostic feature. Only around 10–15% of PD cases can be diagnosed through genetic alterations, while the remaining population, idiopathic PD (iPD), manifest without validated and specific biomarkers either before or after motor symptoms appear. Therefore, clinical diagnosis is reliant on the skills of the clinician, which can lead to misdiagnosis. IPD cases present with a spectrum of non-specific symptoms (e.g., constipation and loss of the sense of smell) that can occur up to 20 years before motor function loss (prodromal stage) and formal clinical diagnosis. Prodromal alterations in metabolites and proteins from the pathways underlying these symptoms could act as biomarkers if they could be differentiated from the broad values seen in a healthy age-matched control population. Additionally, these shifts in metabolites could be integrated with other emerging biomarkers/diagnostic tests to give a PD-specific signature. Here we provide an up-to-date review of the diagnostic value of the alterations in sphingolipids pathway in PD by focusing on the changes in definitive PD (postmortem confirmed brain data) and their representation in “probable PD” cerebrospinal fluid (CSF) and blood. We conclude that the trend of holistic changes in the sphingolipid pathway in the PD brain seems partly consistent in CSF and blood, and could be one of the most promising pathways in differentiating PD cases from healthy controls, with the potential to improve early-stage iPD diagnosis and distinguish iPD from other Parkinsonism when combined with other pathological markers.
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease
Publisher: Springer Science and Business Media LLC
Date: 10-07-2014
Modulating Protein Phosphatase 2A Rescues Disease Phenotype in Neurodegenerative Tauopathies
Publisher: American Chemical Society (ACS)
Date: 19-06-2018
DOI: 10.1021/ACSCHEMNEURO.8B00161
Abstract: Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting for around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide Aβ, which is thought to drive pathology. However, the lack of clinical translation of these Aβ-centric strategies underscores the need for erse treatment strategies targeting other aspects of the disease. Metal dyshomeostasis is a common feature of several neurodegenerative diseases such as AD, Parkinson's disease, and frontotemporal dementia, and manipulation of metal homeostasis has been explored as a potential therapeutic avenue for these diseases. The copper ionophore glyoxalbis-[N4-methylthiosemicarbazonato]Cu(II) (Cu
Characterising the brain metalloproteome in Down syndrome patients with concomitant Alzheimer's pathology
Publisher: Oxford University Press (OUP)
Date: 18-11-2019
DOI: 10.1039/C9MT00196D
Abstract: Down syndrome (DS) is a common intellectual disability, with an incidence of 1 in 700 and is caused by trisomy 21. People with DS develop Alzheimer's disease (AD)-like neuropathology by the age of 40. As metal ion dyshomeostasis (particularly zinc, iron and copper) is one of the characteristics of AD and is believed to be involved in the pathogenesis of disease, we reasoned that it may also be altered in DS. Thus, we used inductively coupled plasma mass spectrometry to examine metal levels in post-mortem brain tissue from DS in iduals with concomitant AD pathology. Size exclusion-ICPMS was also utilised to characterise the metalloproteome in these cases. We report here for the first time that iron levels were higher in a number of regions in the DS brain, including the hippoc us (40%), frontal cortex (100%) and temporal cortex (34%), compared to controls. Zinc and copper were also elevated (both 29%) in the DS frontal cortex, but zinc was decreased (23%) in the DS temporal cortex. Other elements were also examined, a number of which also showed disease-specific changes. The metalloproteomic profile in the DS brain was also different to that in the controls. These data suggest that metals and metal:protein interactions are dysregulated in the DS brain which, given the known role of metals in neurodegeneration and AD, is likely to contribute to the pathogenesis of disease. Interrogation of the underlying cellular mechanisms and consequences of this failure in metal ion homeostasis, and the specific contributions of the in idual DS and AD phenotypes to these changes, should be explored.
Related Organisations
Florey Institute Of Neuroscience And Mental Health
Location: Australia
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