ORCID Profile
0000-0003-3385-9498
Current Organisation
The University of Auckland
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Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2015.01.003
Abstract: Stroke is the third most common cause of death and a major cause of chronic disability in New Zealand. Linked to risk factors that develop across the life-course, stroke is considered to be largely preventable. This study assessed the awareness of stroke risk, symptoms, detection, and prevention behaviors in an urban New Zealand population. Demographics, stroke risk factors awareness, symptoms, responsiveness, and prevention behaviors were evaluated using a structured oral questionnaire. Binomial logistic regression analyses were used to identify predictors of stroke literacy. Although personal experience of stroke increased awareness of symptoms and their likeliness to indicate the need for urgent medical attention, only 42.7% of the respondents (n = 850) identified stroke as involving both blood and the brain. Educational attainment at or above a trade certificate, apprenticeship, or diploma increased the awareness of stroke symptoms compared with those with no formal educational attainment. Pacific Island respondents were less likely than New Zealand Europeans to identify a number of stroke risk factors. Māori, Pacific Island, and Asian respondents were less likely to identify symptoms of stroke and indicate the need for urgent medical attention. The variability in stroke awareness and knowledge may suggest the need to enhance stroke-related health literacy that facilitates understanding of risk and of factors that reduce morbidity and mortality after stroke in people of Māori and Pacific Island descent and in those with lower educational attainment or socioeconomic status. It is therefore important that stroke awareness c aigns include tailored components for target audiences.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.EXPNEUROL.2006.12.008
Abstract: Transcription factors (TFs) are responsible for the specification and fate determination of cells as they develop from progenitor cells into specific types of cells in the brain. Sox-2 and Pax-6 are TFs with key functional roles in the developing brain, although less is known about TFs in the rudimentary germinal zones in the adult human brain. In this study we have investigated the distribution and characterization of Sox-2 and Pax-6 in the human subventricular zone (SVZ). Sox-2 immunoreactivity showed a nuclear labeling pattern and colocalised on GFAP immunoreactive cells as well as on bromodeoxyuridine (BrdU)-positive cells, whereas Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ cells and colocalised with PSA-NCAM-positive progenitor cells. Thus, our data surprisingly reveal that these TFs are differentially expressed in the adult human SVZ where Sox-2 and Pax-6 specify a glial and neuronal fate, respectively.
Publisher: Cold Spring Harbor Laboratory
Date: 10-02-2023
DOI: 10.1101/2023.02.10.527924
Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2 -linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non- UBQLN2 -linked (sporadic) ALS cases, and eight non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates, and aggregates containing both proteins in regions of interest to determine how UBQLN2 -linked and non- UBQLN2 -linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate, and are abundant in the hippoc al formation, spinal cord, all tested regions of neocortex, medulla, and substantia nigra in UBQLN2 -linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2 -linked ALS/FTD. While ubiquilin 2 deposition in frontotemporal regions may enhance cognitive risk in UBQLN2 -linked cases, ubiquilin 2 is deposited mainly in clinically unaffected regions throughout the CNS such that overall symptomology in these cases maps best to the aggregation of TDP-43.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2006
Abstract: One of the challenges for modern neuroscience is to understand the basis of coordinated neuronal function and networking in the human brain. Some of these questions can be addressed using low- and high-resolution imaging techniques on post-mortem human brain tissue. We have established a versatile protocol for fixation of post-mortem adult human brain tissue, storage of the tissue in a human brain bank, and immunohistochemical analysis in order to understand human brain functions in normal controls and in neuropathological conditions. The brains are fixed by perfusion through the internal carotid and basilar arteries to enhance the penetration of fixative throughout the brain, then blocked, postfixed, cryoprotected, snap-frozen and stored at -80 degrees C. Sections are processed for immunohistochemical single- or double-label staining and conventional-, electron- or confocal laser scanning-microscopy analysis. The results gained using this tissue and protocol are vital for determining the localization of neurochemicals throughout the human brain and to document the changes that occur in neurological diseases.
Publisher: Wiley
Date: 22-10-2012
DOI: 10.1002/GLIA.22432
Abstract: Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD-related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and s les from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9-month-old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6-8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD-related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0306-4522(95)00595-1
Abstract: The expression of enkephalin and substance P messenger RNAs was examined in the caudate-putamen of human post mortem tissue from control and Huntington's disease tissue using in situ hybridization techniques and human specific enkephalin and substance P [35S] oligonucleotides. Macroscopic and microscopic quantification of enkephalin and substance P gene expression was carried out using computer-assisted image analysis. Tissue was collected from six control cases with no sign of neurological disease and six Huntington's disease cases ranging from grades 0 to 3 as determined by neuropathological evaluation. The clinical and pathological diagnosis of Huntington's disease was confirmed unequivocally by genetic analysis of the CAG repeat length in both copies of IT15, the Huntington's disease gene. A marked reduction in both enkephalin and substance P messenger RNAs was detected in all regions of the caudate nucleus and putamen in Huntington's disease grades 2/3 when compared to controls in the dorsal caudate few enkephalin or substance P messenger RNA-positive cells were detected. For the early grade (0/1) Huntington's disease cases, a heterogeneous reduction in both enkephalin and substance P messenger RNAs were noted for enkephalin messenger RNA the striatal autoradiograms displayed a conspicuous patchy appearance. Detailed cellular analysis of the dorsal caudate revealed a striking reduction in the number of enkephalin and substance P messenger RNA-positive cells detected and in the intensity of hybridization signal/cell. These data suggest that both the "indirect" GABA/enkephalin and "direct" GABA/substance P pathways are perturbed very early in the course of the disease and that these early changes in chemical signalling may possibly underlie the onset of clinical symptoms.
Publisher: Elsevier BV
Date: 06-1998
DOI: 10.1016/S0306-4522(98)00129-8
Abstract: Recent studies using DNA fragmentation assays suggest a role for apoptosis in cell death in Huntington's disease. In this study, we investigated the relationship between the degree of DNA fragmentation and the number of trinucleotide (CAG) repeats of the Huntington's disease gene in striatal tissue from Huntington's disease brains. We used frozen striatal tissue from 27 post mortem Huntington's disease brains (graded 0-4 on the Vonsattel classification, post mortem delay ranging from 4 to 41 h), plus control sections which were age, sex and post mortem delay matched from neurologically normal and Alzheimer's diseased striatal tissue. Our results show a significant positive correlation between the number of CAG repeats in the Huntington's disease gene and the degree of DNA fragmentation in Huntington's disease striatum. These results suggest that expanded CAG repeats in the Huntington's disease gene may lead to neuronal degeneration in Huntington's disease through an apoptotic mechanism.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0306-4522(02)00550-X
Abstract: Gephyrin is an ubiquitously expressed protein that, in the central nervous system, generates a protein scaffold to anchor inhibitory neurotransmitter receptors in the postsynaptic membrane. It was first identified as a protein component of the glycine receptor complex. Recent studies have demonstrated that gephyrin is colocalized with several subtypes of GABA(A) receptors and is part of postsynaptic GABA(A) receptor clusters. Here, we describe a study of the regional and cellular distribution of gephyrin in the human brain, determined by immunohistochemical localisation at the light and confocal laser scanning microscopic levels. At the regional level, gephyrin immunoreactivity was observed in most of the major brain regions examined. The most intense staining was in the cerebral cortex, hippoc us and caudate-putamen, in various brainstem nuclei with more moderate levels in the thalamus and cerebellum. At the cellular level gephyrin immunoreactivity was present on the plasma membranes of the soma and dendrites of pyramidal neurons throughout the various cortical regions examined. In the hippoc us, intense staining was observed on the granule cells of the dentate gyrus, and neurons of the CA1 and CA3 regions showed intense punctate gephyrin staining on their apical dendrites and cell bodies. Gephyrin immunoreactivity was also observed on neurons in the thalamus, globus pallidus and substantia nigra. In the putamen intense labelling of the striosomes was observed most of the medium-sized neurons in the caudate-putamen were weakly labelled and many large neurons of the striatum were conspicuously stained. Many of the brainstem nuclei, notably the dorsal motor nucleus of the vagus, hypoglossal nucleus, trigeminal nucleus and inferior olive were all labelled with gephyrin. The spinal cord also showed high levels of gephyrin immunoreactivity. Our results demonstrate that the anchoring protein gephyrin is ubiquitously present in the human brain. We therefore suggest that gephyrin may have a central organizer role in assembling and stabilizing inhibitory postsynaptic membranes in human brain and is similar in function to those observed in the rodent brain. These findings contribute towards elucidating the role of gephyrin in the human brain.
Publisher: Wiley
Date: 19-04-2007
DOI: 10.1002/CNE.21349
Abstract: Glycine receptors (GlyRs) are heteropentameric chloride ion channels that facilitate fast-response, inhibitory neurotransmission in the mammalian spinal cord and brain. GlyRs have four functional subunits, alpha1-3 and beta, which likely exist in heteromeric alphabeta combinations. Mutations in GlyR alpha1 and beta subunits are well known for their involvement in hyperekplexia, a paroxysmal motor disorder. In this study we present the first detailed immunohistochemical investigation at the regional, cellular, and subcellular levels of GlyRs in the human basal ganglia. The results show that GlyRs are present at the regional level in low concentrations in the striatum and globus pallidus and are present in the highest concentrations in the substantia nigra. At the cellular level, GlyRs are present only in discrete populations of neurons immunoreactive for choline acetyltransferase (ChAT), parvalbumin, and calretinin in the human striatum, on a subpopulation of parvalbumin- and calretinin-positive neurons in the globus pallidus, and in the substantia nigra GlyRs are present on approximately three-fourths of all pars compacta and one-third of all pars reticulata neurons. They also form a distinct band of immunoreactive neurons in the intermedullary layers of the globus pallidus. At the subcellular level in the substantia nigra pars reticulata (SNr), GlyRs show a localized distribution on the soma and dendrites that partially complements but does not overlap with the distribution of gamma-aminobutyric acid (GABA)A receptors. Our results demonstrate the precise cellular and subcellular localization of GlyRs in the human basal ganglia and suggest that glycinergic receptors may play an important complementary role to other inhibitory receptors in modulating cholinergic, dopaminergic, and GABAergic neuronal pathways in the basal ganglia.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.BRAINRES.2003.09.051
Abstract: Immunoreactivity of GABA(A) receptor subunits and the receptor anchoring protein gephyrin was investigated in the human globus pallidus using antibodies raised against the alpha(1) and gamma(2) subunits of the GABA(A) receptor complex and gephyrin. The results revealed increased GABA(A) receptor subunit immunoreactivity and unchanged levels of gephyrin immunoreactivity in Huntington's diseased (HD) globus pallidus (GP). The results demonstrate that gephyrin immunoreactivity did not change in unison with GABA(A) receptor changes in HD, suggesting that the receptor anchoring protein gephyrin is unaltered and maintains a stable lattice structure in the face of GABA(A) receptor changes in HD.
Publisher: Oxford University Press (OUP)
Date: 13-02-2010
DOI: 10.1093/HMG/DDQ063
Publisher: Oxford University Press (OUP)
Date: 31-01-2014
DOI: 10.1093/HMG/DDU047
Abstract: Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock-on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD.
Publisher: Wiley
Date: 17-12-2007
DOI: 10.1002/CNE.21573
Abstract: Gamma-aminobutyric acid(A) (GABA(A)) receptors (GABA(A)R) are inhibitory heteropentameric chloride ion channels comprising a variety of subunits and are localized at postsynaptic sites within the central nervous system. In this study we present the first detailed immunohistochemical investigation on the regional, cellular, and subcellular localisation of alpha(1), alpha(2), alpha(3), beta(2,3), and gamma(2) subunits of the GABA(A)R in the human substantia nigra (SN). The SN comprises two major regions, the SN pars compacta (SNc) consisting of dopaminergic projection neurons, and the SN pars reticulata (SNr) consisting of GABAergic parvalbumin-positive projection neurons. The results of our single- and double-labeling studies demonstrate that in the SNr GABA(A) receptors contain alpha(1), alpha(3), beta(2,3), and gamma(2) subunits and are localized in a weblike network over the cell soma, dendrites, and spines of SNr parvalbumin-positive nonpigmented neurons. By contrast, GABA(A)Rs on the SNc dopaminergic pigmented neurons contain predominantly alpha(3) and gamma(2) subunits however there is GABA(A)R heterogeneity in the SNc, with a small subpopulation (6.5%) of pigmented SNc neurons additionally containing alpha(1) and beta(2,3) GABA(A)R subunits. Also, in the SNr, parvalbumin-positive terminals are adjacent to GABA(A)R on the soma and proximal dendrites of SNr neurons, whereas linear arrangements of substance P-positive terminals are adjacent to GABA(A) receptors on all regions of the dendritic tree. These results show marked GABA(A)R subunit hetereogeneity in the SN, suggesting that GABA exerts quite different effects on pars compacta and pars reticulata neurons in the human SN via GABA(A) receptors of different subunit configurations.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer New York
Date: 2009
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1016/S0969-9961(03)00014-7
Abstract: Recently, an inherited spinocerebellar ataxia (SCA17) has been attributed to polyglutamine coding expansions within the gene coding for human TATA-box binding protein (TBP). The normal repeat range is 25-42 units with patients having as few as 46 repeats. We undertook a TBP repeat length population study showing its relative stability, skewed distribution, and substantial population specific differences. To investigate the mechanism of neurodegeneration in SCA17 we have developed a cellular model expressing full-length TBP with a range of polyQ expansions. As has been found with other polyQ cellular models, insoluble intracellular inclusions form in a repeat-length-dependent manner. In addition, we have shown that the expanded TBP polyQ tract is able to interact with other overexpressed polyQ-containing proteins. Importantly, overexpression of expanded TBP results in increased Cre-dependent transcriptional activity. As TBP is required for transcription by all RNA polymerases, this may indicate a mechanism for aberrant polyQ gain of function.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0306-4522(03)00543-8
Abstract: Gephyrin is a postsynaptic clustering molecule that forms a protein scaffold to anchor inhibitory neurotransmitter receptors at the postsynaptic membrane of neurons. Gephyrin was first identified as a protein component of the glycine receptor complex and is also colocalized with several GABAA receptor subunits in rodent brain. We have studied the distribution of gephyrin and glycine receptor subunits in the human brainstem and spinal cord using immunohistochemistry at light and confocal laser scanning microscopy levels. This study demonstrates the novel localization of gephyrin with glycine receptors in the human brainstem and spinal cord. Colocalization of immunoreactivities for gephyrin and glycine receptor subunits was detected in the dorsal and ventral horns of the spinal cord, the hypoglossal nucleus and the medial vestibular nucleus of the medulla. The results clearly establish that gephyrin is ubiquitously distributed and is colocalized, with a large proportion of glycine receptor subunits in the human brainstem and spinal cord. We therefore suggest that gephyrin functions as a clustering molecule for major subtypes of glycine receptors in the human CNS.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-06-2020
Abstract: Mutations in UBQLN2 cause amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 regulates proteostasis by clearing misfolded proteins from cells through the proteasome and autophagy degradation pathways. Here, we report on defects in autophagy that results from knockout or expression of WT and ALS/FTD mutant UBQLN2 proteins in cells and mice. We show that loss of UBQLN2 reduces expression of ATP6v1g1, a critical subunit of the ATPase pump that regulates vacuolar acidification and is required for the maturation of autophagosomes. We show that WT but not ALS/FTD mutant UBQLN2 proteins can rescue the acidification defect. Furthermore, WT but not ALS/FTD mutant UBQLN2 proteins bind and stimulate ATP6v1g1 biogenesis, suggesting an important role played by UBQLN2 in V-ATPase regulation.
Publisher: Frontiers Media SA
Date: 2009
Publisher: Mary Ann Liebert Inc
Date: 19-03-2000
Abstract: PCR lification of the CAG repeat in exon 1 of the IT15 gene is routinely undertaken to confirm a clinical diagnosis of Huntington disease (HD) and to provide predictive testing for at-risk relatives of affected in iduals. Our studies have detected null alleles on the chromosome carrying the expanded repeat in three of 91 apparently unrelated HD families. Sequence analysis of these alleles has revealed the same mutation event, leading to the juxtaposition of uninterrupted CAG and CCG repeats. These data suggest that a mutation-prone region exists in the IT15 gene bounded by the CAG and CCG repeats and that caution should be exercised in designing primers that anneal to the region bounded by these repeats. Two of the HD families segregated null alleles with expanded uninterrupted CAG repeats at the lower end of the zone of reduced penetrance. The expanded repeats are meiotically unstable in these families, although this instability is within a small range of repeat lengths. The haplotypes of the disease-causing chromosomes in these two families differ, only one of which is similar to that reported previously as being specific for new HD mutations. Finally, no apparent mitotic instability of the uninterrupted CAG repeat was observed in the brain of one of the HD in iduals.
Publisher: Wiley
Date: 08-04-2009
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/0306-4522(94)00504-X
Abstract: Repeated episodes of cerebral hypoxia-ischemia can cause primarily striatal neuronal loss in the developing brain. We investigated the effect of repeated episodes of asphyxia on specific neuronal sub-populations of the basal ganglia in late-gestation fetal sheep. Asphyxia was induced in 10 fetal sheep (118-126 days gestation) by occluding the umbilical cord for 5 min. This procedure was repeated four times at 30 min intervals and the brains were fixed 3 days later for histopathology. Immunohistochemical markers were used to identify various populations of neurons in the striatum. Antibodies to calbindin were used to stain the GABAergic medium-sized striatal projection neurons and antibodies to somatostatin and parvalbumin to identify striatal interneurons. Striatal projection neurons to the globus pallidus were recognized by enkephalin immunoreactivity, while the striatonigral terminals were identified in the substantia nigra pars reticulata by substance P immunohistochemical labelling. The results showed a marked loss of calbindin staining in the striatum, evident by both reduced cell numbers and a decrease in neuropil staining. The number of parvalbumin immunoreactive cells was also reduced in the striatum, while somatostatin interneurons were selectively preserved. In addition, immunostaining for enkephalin in the globus pallidus and for substance P in the substantia nigra was markedly reduced. These results show that the stiatal GABAergic medium-sized projection neurons are severely affected by recurrent episodes of asphyxia. These findings are confirmed and extended by the results demonstrating that both the enkephalin/GABA striatopallidal and the substance P/GABA stiatonigral pathways are affected. The results of this study therefore suggest that the efferent striatal projections to the globus pallidus and to the substantia nigra may be involved in asphyxial episodes resulting in cerebral palsy.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0306-4522(95)00596-X
Abstract: The cellular abundance of neuronal nitric oxide synthase and somatostatin messenger RNAs was compared in the caudate nucleus, putamen and sensorimotor cortex of Huntington's disease and control cases. Neuronal nitric oxide synthase messenger RNA was significantly decreased in the caudate nucleus and putamen, but not in the sensorimotor cortex in Huntington's disease the decrease in neuronal nitric oxide synthase messenger RNA became more pronounced with the severity of the disease. Somatostatin gene expression was significantly decreased in the dorsal putamen in Huntington's disease, but was essentially unchanged in all other regions examined. The density of neurons expressing detectable levels of neuronal nitric oxide synthase messenger RNA was reduced in the striata of Huntington's disease cases with advanced pathology the density of neurons expressing detectable levels of somatostatin messenger RNA was similar in control and Huntington's disease cases. Neuropeptide Y-, somatostatin- and NADPH-diaphorase-positive neurons were consistently present throughout the striatum across all the grades of the disease. Neuronal nitric oxide synthase and NADPH-diaphorase activity (a histochemical marker for nitric oxide synthase-containing neurons) co-localize with somatostatin and neuropeptide Y in interneurons in the human striatum and cerebral cortex. Although the neurodegeneration associated with Huntington's disease is most evident in the striatum (particularly the dorsal regions), neuronal nitric oxide synthase/neuropeptide Y/somatostatin interneurons are relatively spared. Nitric oxide released by neuronal nitric oxide synthase-containing neurons may mediate glutamate-induced excitotoxic cell death, a mechanism proposed to be instrumental in causing the neurodegeneration seen in Huntington's disease. The results described here suggest that although the population of interneurons containing somatostatin, neuropeptide Y and neuronal nitric oxide synthase do survive in the striatum in Huntington's disease they are damaged during the course of the disease. The results also show that the reduction in neuronal nitric oxide synthase and somatostatin messenger RNAs is most pronounced in the more severely affected dorsal regions of the striatum. Furthermore, the loss of neuronal nitric oxide messenger RNA becomes more pronounced with the severity of the disease thus implying a down-regulation in neuronal nitric oxide synthase messenger RNA synthesis, and potentially neuronal nitric oxide synthase protein levels, in Huntington's disease.
Publisher: Wiley
Date: 14-04-2010
DOI: 10.1002/CNE.22397
Abstract: In the adult rodent forebrain, astrocyte-like neural stem cells reside within the subventricular zone (SVZ) and give rise to progenitors and neuroblasts, which then undergo chain migration along the rostral migratory stream (RMS) to the olfactory bulb, where they mature into fully functional interneurons. Neurogenesis also occurs in the adult human SVZ, where neural precursors similar to the rodent astrocyte-like stem cell and neuroblast have been identified. A migratory pathway equivalent to the rodent RMS has also recently been described for the human forebrain. In the embryo, the guidance receptor neogenin and its ligands netrin-1 and RGMa regulate important neurogenic processes, including differentiation and migration. We show in this study that neogenin is expressed on neural stem cells (B cells), progenitor cells (C cells), and neuroblasts (A cells) in the adult mouse SVZ and RMS. We also show that netrin-1 and RGMa are ideally placed within the neurogenic niche to activate neogenin function. Moreover, we find that neogenin and RGMa are also present in the neurogenic regions of the human adult forebrain. We show that neogenin is localized to cells displaying stem cell (B cell)-like characteristics within the adult human SVZ and RMS and that RGMa is expressed by the same or a closely apposed cell population. This study supports the hypothesis that, as in the embryo, neogenin regulates fundamental signalling pathways important for neurogenesis in the adult mouse and human forebrain.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.NEUROBIOLAGING.2017.06.020
Abstract: This study reports the identification and characterization of markers of Alzheimer's disease (AD) in aged sheep (Ovis aries) as a preliminary step toward making a genetically modified large animal model of AD. Importantly, the sequences of key proteins involved in AD pathogenesis are highly conserved between sheep and human. The processing of the amyloid-β (Aβ) protein is conserved between sheep and human, and sheep Aβ
No related grants have been discovered for Richard Faull.