ORCID Profile
0000-0002-1388-2108
Current Organisations
Royal Brisbane and Women's Hospital
,
Macquarie University
,
University of Queensland
,
Wesley Medical Research
,
University Of Queensland Centre for Clinical Research
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Publisher: The Company of Biologists
Date: 2012
DOI: 10.1242/JCS.095109
Abstract: At neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signaling through the Muscle Specific Kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act via muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signaling can modulate n-agrin-induced AChR clustering independent of its effects on transcription. Here we report that when injected into muscles of embryonic mice, neuregulin-1increased the size of developing AChR clusters. We investigated this phenomenon using cultured myotubes, and found thatin the ongoing presence of n-agrin,neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. Thispotentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence may function as a second order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signaling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2022
DOI: 10.1101/2022.08.30.505901
Abstract: The importance of dyslipidemia in amyotrophic lateral sclerosis (ALS) patients is increasingly recognised as a potential key mechanism driving disease onset, progression and survival. Evidence in familial ALS models suggests that lipid composition is significantly affected, however clinically relevant models have yet to be investigated. Using a powerful lipidomic approach, we uncover significant dysregulation of glycosphingolipid (GSL) metabolism in both the spinal cord and skeletal muscles of transgenic TDP-43 Q331K mice. Treatment with the selective glucocerebrosidase 2 (GBA2) inhibitor ambroxol at symptom onset significantly improved motor and gait functions in TDP-43 Q331K mice. Ambroxol treatment preserved motor neurons and neuromuscular junctions which was associated with modulation of GSL metabolism. Our study establishes significant lipid dysregulation in a clinically relevant model of ALS. Importantly, we show positive therapeutic outcomes in a mouse model of TDP-43 proteinopathy, suggesting that ambroxol may be a promising candidate to treat underlying dyslipidemia and symptoms of ALS.
Publisher: JMIR Publications Inc.
Date: 22-09-2021
DOI: 10.2196/28766
Abstract: Despite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients’ ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters mediate the development of benefit-to-burden criteria for innovative technology and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2004
DOI: 10.1097/00001756-200411150-00014
Abstract: Agrin and neuregulin (HRG-beta1) play complementary roles in synapse formation. While HRG-beta1 induces transcriptional up-regulation of postsynaptic proteins, here we present evidence that it can potentiate agrin-induced acetylcholine receptor (AChR) clustering in C2 myotubes. Agrin induced maximal AChR clustering in 4 h. HRG-beta1 treatment for 4 h produced no increase over basal AChR cluster numbers. When myotubes were treated for 4 h with 100 pM agrin, HRG-beta1 augmented AChR cluster numbers by 2-fold compared to myotubes treated with 100 pM agrin alone. Thus, HRG-beta1 can potentiate agrin-induced AChR clustering.
Publisher: EMBO
Date: 27-03-2015
Abstract: Amyotrophic lateral sclerosis ( ALS ) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease ( SOD 1 G86R ), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD 1 G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.NEURON.2007.06.031
Abstract: Agrin induces, whereas acetylcholine (ACh) disperses, ACh receptor (AChR) clusters during neuromuscular synaptogenesis. Such counteractive interaction leads to eventual dispersal of nonsynaptic AChR-rich sites and formation of receptor clusters at the postjunctional membrane. However, the underlying mechanisms are not well understood. Here we show that calpain, a calcium-dependent protease, is activated by the cholinergic stimulation and is required for induced dispersion of AChR clusters. Interestingly, the AChR-associated protein rapsyn interacted with calpain in an agrin-dependent manner, and this interaction inhibited the protease activity of calpain. Disrupting the endogenous rapsyn/calpain interaction enhanced CCh-induced dispersion of AChR clusters. Moreover, the loss of AChR clusters in agrin mutant mice was partially rescued by the inhibition of calpain via overexpressing calpastatin, an endogenous calpain inhibitor, or injecting calpeptin, a cell-permeable calpain inhibitor. These results demonstrate that calpain participates in ACh-induced dispersion of AChR clusters, and rapsyn stabilizes AChR clusters by suppressing calpain activity.
Publisher: Wiley
Date: 13-01-2022
DOI: 10.1111/BPH.15738
Abstract: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi‐target drug used to treatment of coronary artery disease, trimetazidine, in SOD1 G93A mice. As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti‐inflammatory and antioxidant effect. We orally treated SOD1 G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg −1 , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1 G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. In SOD1 G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.
Publisher: Wiley
Date: 09-08-2021
DOI: 10.1111/ENE.15003
Abstract: To establish the utility of venous creatinine as a biomarker to monitor loss of fat‐free mass in patients with amyotrophic lateral sclerosis (ALS). In this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow‐up were determined in a cohort of patients with ALS from Australia ( n = 69) and the Netherlands ( n = 38). The mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat‐free mass was similar between all groups ( r = 0.36, p 0.001). Within patients, fat‐free mass declined by 0.31 (95% confidence interval [CI]: 0.22–0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38–0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35–0.76, p 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90–0.98, p = 0.007). Venous creatinine is decreased in ALS and declines alongside a decline in fat‐free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat‐free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat‐free mass and disease progression in ALS.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.BIOCEL.2006.10.012
Abstract: Neural agrin is a heparan sulphate proteoglycan first defined by its ability to induce the clustering of acetylcholine receptors (AChRs) on cultured muscle cells. Neural agrin activates the transmembrane Muscle Specific Kinase (MuSK) on the postsynaptic muscle cell to stabilise the developing neuromuscular synapse. Three biological mechanisms for agrin/MuSK signalling are briefly discussed: selective transcription of synaptic genes such as MuSK itself, to reinforce developing postsynaptic clusters of AChRs initiation of second messenger signalling pathways that can induce the formation of AChR clusters and retrograde signalling downstream of agrin/MuSK that may transform the growth cone of the motor axon into a stable differentiated nerve terminal, specialised for regulated exocytosis of neurotransmitter. Here we briefly review some key mechanisms through which neural agrin acts to foster the formation of mature neuromuscular synapses.
Publisher: Informa UK Limited
Date: 29-05-2019
Publisher: Wiley
Date: 31-08-2010
Publisher: American Society of Hematology
Date: 24-12-2020
Abstract: Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2020
DOI: 10.1038/S41525-020-0118-3
Abstract: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands s le (area under the curve, AUC = 0.65, CI 95% = [0.62–0.68], p = 8.3 × 10 −22 ). The maximum AUC achieved was 0.69 (CI 95% = [0.66–0.71], p = 4.3 × 10 −34 ) when cell-type proportion was included in the predictor.
Publisher: Informa UK Limited
Date: 07-2017
DOI: 10.2147/DNND.S120607
Publisher: JMIR Publications Inc.
Date: 14-03-2021
Abstract: espite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients’ ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters mediate the development of benefit-to-burden criteria for innovative technology and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
Publisher: The Endocrine Society
Date: 17-05-2011
DOI: 10.1210/EN.2011-0253
Abstract: Measures of pulsatile GH secretion require frequent collection and analysis of blood s les at regular intervals. Due to blood volume constraints, repeat measures of circulating levels of GH in mice remain challenging. Consequently, few observations exist in which the pulsatile pattern of GH secretion in mice have been characterized. To address this, we developed a technique for the collection and analysis of circulating levels of GH at regular and frequent intervals in freely moving mice. This was achieved through the development of a sensitive assay for the detection of GH in small (2 μl) quantities of whole blood. The specificity and accuracy of this assay was validated following guidelines established for single-laboratory validation as specified by the International Union of Pure and Applied Chemistry. We incorporated an established method for tail-clip blood s le collection to determine circulating levels of GH secretion in 36 whole blood s les collected consecutively over a period of 6 h. Resulting measures were characterized by peak secretion periods and interpulse stable baseline secretion periods. Periods characterized by elevated whole blood GH levels consisted of multicomponent peaks. Deconvolution analysis of resulting measures confirmed key parameters associated with pulsatile GH secretion. We show a striking decrease in pulsatile GH secretion in mice after 12-18 h of fasting. This model is necessary to characterize the pulsatile profile of GH secretion in mice and will significantly contribute to current attempts to clarify mechanisms that contribute to the regulation of GH secretion.
Publisher: BMJ
Date: 08-09-2018
Publisher: Public Library of Science (PLoS)
Date: 26-08-2016
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.29.546993
Abstract: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease characterised by metabolic changes at onset and throughout disease progression. Here, we investigate the role of arylamine N-acetyltransferase 1 (NAT1), a cytosolic protein associated with mitochondrial function, in ALS. We demonstrate that expression of the murine homolog (mNat2) increases in skeletal muscle of SOD G93A mice, but not control animals, at onset of symptoms and remains elevated until end stage of the disease. Measurement of mitochondrial respiration in peripheral blood mononuclear cells of patients with ALS identified patient sub-populations with low and high metabolic potential, which was strongly associated with NAT1 activity. Those patients with high NAT1 activity had elevated basal respiration, ATP production, mitochondrial reserve, and aerobic glycolysis. NAT1 predicted increased whole body metabolic index, which may be clinically significant as these patients show increased functional decline and shorter survival. NAT1 may be a novel target in those patients with elevated activity.
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2023
DOI: 10.1101/2023.03.13.23287229
Abstract: Amyotrophic lateral sclerosis (ALS), the most predominant form of Motor Neuron Disease (MND), is a progressive and fatal neurodegenerative condition that spreads throughout the neuromotor system by afflicting upper and lower motor neurons. Lower motor neurons project from the central nervous system and innervate muscle fibres at motor endplates, which degrade over the course of the disease leading to muscle weakness. The direction of neurodegeration from or to the point of neuromuscular junctions and the role of muscle itself in pathogenesis has continued to be a topic of debate in ALS research. To assess the variation in gene expression between affected and nonaffected muscle tissue that might lead to this local degeneration of motor units, we generated RNA-seq skeletal muscle transcriptomes from 28 MND cases and 18 healthy controls and conducted differential expression analyses on gene-level counts, as well as an isoform switching analysis on isoform-level counts. We identified 52 differentially-expressed genes (Benjamini-Hochberg-adjusted p 0.05) within this comparison, including 38 protein coding, 9 long non-coding RNA, and 5 pseudogenes. Of protein-coding genes, 31 were upregulated in cases including with notable genes including the collagenic COL25A1 ( p = 3.1 × 10 −10 ), SAA1 which is released in response to tissue injury ( p = 3.6 × 10 −5 ) as well as others of the SAA family, and the actin-encoding ACTC1 ( p = 2.3 × 10 −5 ). Additionally, we identified 17 genes which exhibited a functional isoform switch with likely functional consequences between cases and controls. Our analyses provide evidence of increased tissue generation in MND cases, which likely serve to compensate for the degeneration of motor units and skeletal muscle.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Informa UK Limited
Date: 09-07-2020
Publisher: Informa UK Limited
Date: 16-11-2020
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 18-07-2022
DOI: 10.1007/S00415-022-11273-X
Abstract: To capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology. We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use. In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements reporting concerns about the burden and distress of home-monitoring, privacy and data security. Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.CLINPH.2012.01.028
Abstract: To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS. We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1(G93A) mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve. In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1(G93A) mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease. The number of motor neurons in the spinal cord of wild-type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1(G93A) mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction. Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41588-021-00973-1
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 in iduals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 25-11-2015
DOI: 10.1111/JNE.12327
Abstract: Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BIOCEL.2010.10.008
Abstract: Muscle Specific Kinase (MuSK) is a transmembrane tyrosine kinase vital for forming and maintaining the mammalian neuromuscular junction (NMJ: the synapse between motor nerve and skeletal muscle). MuSK expression switches on during skeletal muscle differentiation. MuSK then becomes restricted to the postsynaptic membrane of the NMJ, where it functions to cluster acetylcholine receptors (AChRs). The expression, activation and turnover of MuSK are each regulated by signals from the motor nerve terminal. MuSK forms the core of an emerging signalling complex that can be acutely activated by neural agrin (N-agrin), a heparin sulfate proteoglycan secreted from the nerve terminal. MuSK activation initiates complex intracellular signalling events that coordinate the local synthesis and assembly of synaptic proteins. The importance of MuSK as a synapse organiser is highlighted by cases of autoimmune myasthenia gravis in which MuSK autoantibodies can deplete MuSK from the postsynaptic membrane, leading to complete disassembly of the adult NMJ.
Publisher: The Endocrine Society
Date: 12-2013
DOI: 10.1210/EN.2013-1570
Abstract: GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1G93A mice throughout the course of ALS disease. Male wild-type and hSOD1G93A mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1G93A mice compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1G93A mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JNS.2014.02.035
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease that is characterized by the loss of upper (corticospinal) and lower motor neurons. ALS is a multifactorial disease whereby a combination of genetic and environmental factors may contribute to disease pathogenesis. While the majority of studies indicate that the underlying causes for ALS pathology may be due to multiple defects at the cellular level, factors that have recently been identified to be associated with survival could lead to the development of beneficial interventions. In ALS, a higher pre-morbid body mass index (BMI) and the maintenance of BMI and nutritional state is associated with improved outcome. This review will focus on the associations between body composition and adiposity relative to disease duration and risk, and will discuss current evidence that supports the benefits of improving energy balance, and the maintenance of body mass through nutritional intervention in ALS.
Publisher: Oxford University Press (OUP)
Date: 24-09-2020
DOI: 10.1093/BRAINCOMMS/FCAA154
Abstract: Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the SOD1G93A mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an in idual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.YFRNE.2014.04.004
Abstract: Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.
Publisher: Wiley
Date: 08-11-2023
DOI: 10.1111/ENE.15589
Abstract: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS. We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS ( n = 42), patients with AD ( n = 167) and non‐neurodegenerative disease controls ( n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes. Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite ( p = 0.58) or hypermetabolism ( p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight ( p = 0.08) and fat mass ( p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07). These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000446502
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.
Publisher: Wiley
Date: 03-11-2016
DOI: 10.1113/JP272988
Publisher: Cold Spring Harbor Laboratory
Date: 24-03-2021
DOI: 10.1101/2021.03.12.21253115
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 s les (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.
Publisher: BMJ
Date: 23-06-2020
Publisher: Wiley
Date: 22-12-2017
DOI: 10.1002/MUS.26039
Abstract: The pathology of amyotrophic lateral sclerosis (ALS) is associated with impaired RNA processing and microRNA (miRNA) dysregulation. Here we investigate the regulation of the members of the miRNA biogenesis pathways and total miRNA levels at different stages of the disease. Muscle, brain, and spinal cord tissue were obtained from presymptomatic, symptomatic, and end-stage superoxide dismutase 1 (SOD1) As the diseases progresses, several genes involved in miRNA biogenesis as well as the miRNA/total RNA (totRNA) ratio increased in the tibialis anterior (TA) muscle but not in the soleus or in neural tissue. We propose that a dysregulation in the miRNA/totRNA ratio in the TA muscle from SOD1
Publisher: Informa UK Limited
Date: 16-08-2021
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2020
DOI: 10.1101/2020.04.02.021238
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1 G93A mouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an in idual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.
Publisher: Informa UK Limited
Date: 27-04-2017
DOI: 10.1080/21678421.2017.1317811
Abstract: Anthropometric measurements including body mass index (BMI) and body adiposity index (BAI) are widely employed as indicators of fat mass (FM). Metabolic abnormalities in amyotrophic lateral sclerosis (ALS) impact disease progression, therefore assessment of FM informs care. The aim of this study was to determine whether BMI and BAI are accurate predictors of FM in ALS. Methodology and main findings: BMI, BAI and percentage FM (determined by air displacement plethysmography FM-ADP) were measured in control (n = 35) and ALS (n = 44) participants. While BMI and BAI correlated significantly with FM-ADP, neither index provided an accurate estimate of FM. In longitudinally assessed ALS participants (n = 29 ∼six-month repeat assessment interval), although a change in BMI (r Using FM-ADP as the standard, this study suggests that BMI and BAI are not accurate measures of FM in ALS. Furthermore, longitudinal assessments indicate that changes in BMI and BAI do not consistently reflect true changes of FM in ALS.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2023
DOI: 10.1007/S00415-023-11584-7
Abstract: Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND. In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97 hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline. Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12 variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16). Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Bioscientifica
Date: 24-05-2013
DOI: 10.1530/JOE-13-0084
Abstract: Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight epididymal fat mass and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.
Publisher: MDPI AG
Date: 09-06-2021
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.
Publisher: Wiley
Date: 23-11-2017
DOI: 10.1111/ACEL.12703
Publisher: American Chemical Society (ACS)
Date: 17-02-2010
DOI: 10.1021/JA910602H
Abstract: Alpha-conotoxins are tightly folded miniproteins that antagonize nicotinic acetylcholine receptors (nAChR) with high specificity for erse subtypes. Here we report the use of selenocysteine in a supported phase method to direct native folding and produce alpha-conotoxins efficiently with improved biophysical properties. By replacing complementary cysteine pairs with selenocysteine pairs on an hiphilic resin, we were able to chemically direct all five structural subclasses of alpha-conotoxins exclusively into their native folds. X-ray analysis at 1.4 A resolution of alpha-selenoconotoxin PnIA confirmed the isosteric character of the diselenide bond and the integrity of the alpha-conotoxin fold. The alpha-selenoconotoxins exhibited similar or improved potency at rat diaphragm muscle and alpha3beta4, alpha7, and alpha1beta1 deltagamma nAChRs expressed in Xenopus oocytes plus improved disulfide bond scrambling stability in plasma. Together, these results underpin the development of more stable and potent nicotinic antagonists suitable for new drug therapies, and highlight the application of selenocysteine technology more broadly to disulfide-bonded peptides and proteins.
Publisher: Informa UK Limited
Date: 30-05-2019
Publisher: The Endocrine Society
Date: 09-2012
DOI: 10.1210/EN.2012-1178
Abstract: The transition between puberty and adulthood is accompanied by a slowing in linear growth. Although GH is a key factor that drives somatic development into adulthood, early adulthood coincides with a reduction in circulating levels of GH. To this extent, a pathological decline in postpubertal GH secretion is detrimental to attainment of peak lean muscle mass and bone mass and promotes adiposity and increases susceptibility to the development of obesity in adulthood. Here we characterized pulsatile GH secretion in C57BL/6J mice at 12 and 16 wk of age. Deconvolution analysis of these measures reveals a reduction in pulsatile GH secretion between 12 and 16 wk of age. Dietary intervention with high-fat feeding at 8 wk of age results in a significant increase in adiposity, the development of glucose intolerance, and hyperinsulinemia. We show the exacerbation of the age-associated decline in pulsatile GH secretion in high-fat-fed mice after 4 wk of dietary intervention (at 12 wk of age), and a further suppression of pulsatile GH secretion by 8 wk of dietary intervention (at 16 wk of age). Suppressed pulsatile secretion of GH did not coincide with an elevation in circulating free fatty acids. Rather, we observed increased hepatic triglyceride content and an eventual decrease in circulating levels of IGF-I. Given the established role of GH in maintaining healthy aging, we anticipate that an advancing of the age-associated decline in pulsatile GH secretion as a consequence of dietary-induced weight gain may have long-term ramifications on adult health.
Publisher: Wiley
Date: 29-01-2021
DOI: 10.1111/JNE.12938
Abstract: Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider‐ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin‐mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide‐ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease‐relevant processes observed in ALS. Expanding on the well‐known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin‐mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin‐like growth factor‐1 (IGF‐1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF‐1 are associated with faster disease progression and worse disease outcome in patients with ALS.
Publisher: Elsevier BV
Date: 10-2020
Publisher: The Endocrine Society
Date: 23-05-2012
DOI: 10.1210/EN.2011-2171
Abstract: GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1G93A transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1G93A transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1G93A mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1G93A mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1G93A mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2023
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1186/S13578-020-00511-2
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.
Publisher: Wiley
Date: 08-2008
DOI: 10.1002/DNEU.20654
Abstract: Fluorescence resonance energy transfer (FRET) experiments at neuromuscular junctions in the mouse tibialis anterior muscle show that postsynaptic acetylcholine receptors (AChRs) become more tightly packed during the first month of postnatal development. Here, we report that the packing of AChRs into postsynaptic aggregates was reduced in 4-week postnatal mice that had reduced amounts of the AChR-associated protein, rapsyn, in the postsynaptic membrane (rapsyn(+/-) mice). We hypothesize that nerve-derived agrin increases postsynaptic expression and targeting of rapsyn, which then drives the developmental increase in AChR packing. Neural agrin treatment elevated the expression of rapsyn in C2 myotubes by a mechanism that involved slowing of rapsyn protein degradation. Similarly, exposure of synapses in postnatal muscle to exogenous agrin increased rapsyn protein levels and elevated the intensity of anti-rapsyn immunofluorescence, relative to AChR, in the postsynaptic membrane. This increase in the rapsyn-to-AChR immunofluorescence ratio was associated with tighter postsynaptic AChR packing and slowed AChR turnover. Acute blockade of synaptic AChRs with alpha-bungarotoxin lowered the rapsyn-to-AChR immunofluorescence ratio, suggesting that AChR signaling also helps regulate the assembly of extra rapsyn in the postsynaptic membrane. The results suggest that at the postnatal neuromuscular synapse agrin signaling elevates the expression and targeting of rapsyn to the postsynaptic membrane, thereby packing more AChRs into stable, functionally-important AChR aggregates.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Informa UK Limited
Date: 27-09-2022
Publisher: Frontiers Media SA
Date: 23-01-2018
Publisher: Elsevier BV
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.BEEM.2017.10.009
Abstract: Growth hormone (GH) secretory patterns emerge following birth, and changes in patterning occur throughout life. These secretory patterns are coupled to growth, reproduction and metabolism. Comparing human and animal studies, this review will highlight ultradian patterning of GH release and the mechanisms that contribute to this. Discussions will focus on the emergence in variations in the number and frequency of GH secretory events, and the amounts of GH released (peak and basal). Animal studies have contributed significantly to our understanding of the processes that regulate GH release. However, translation of knowledge from animal models to benefit our understanding of human physiology is sometimes limited. To overcome these limitations, it is critical that we reconcile the cause and consequences of differences in GH release between humans and model organisms. In doing so, we can embrace emerging technologies that will rapidly advance our knowledge of endogenous process that control GH release.
Publisher: Oxford University Press (OUP)
Date: 16-06-2023
Abstract: Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other MN diseases and draw perspectives for future research and treatment.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2016
DOI: 10.1038/SREP37968
Abstract: Layer V pyramidal neurons (LVPNs) within the motor cortex integrate sensory cues and co-ordinate voluntary control of motor output. In amyotrophic lateral sclerosis (ALS) LVPNs and spinal motor neurons degenerate. The pathogenesis of neural degeneration is unknown in ALS 10% of cases have a genetic cause, whereas 90% are sporadic, with most of the latter showing TDP-43 inclusions. Clinical and experimental evidence implicate excitotoxicity as a prime aetiological candidate. Using patch cl and dye-filling techniques in brain slices, combined with high-resolution confocal microscopy, we report increased excitatory synaptic inputs and dendritic spine densities in early presymptomatic mice carrying a TDP-43 Q331K mutation. These findings demonstrate substantive alterations in the motor cortex neural network, long before an overt degenerative phenotype has been reported. We conclude that increased excitatory neurotransmission is a common pathophysiology amongst differing genetic cases of ALS and may be of relevance to the 95% of sporadic ALS cases that exhibit TDP-43 inclusions.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2017
DOI: 10.1038/S41467-017-00471-1
Abstract: Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS ( p = 1.3 × 10 −8 ), with replication support from two independent Australian s les (combined 576 cases and 683 controls, p = 1.7 × 10 −3 ). Both GPX3 and TNIP1 interact with other known ALS genes ( SOD1 and OPTN , respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.
Publisher: Springer Science and Business Media LLC
Date: 2015
Publisher: The Open Journal
Date: 05-08-2022
DOI: 10.21105/JOSS.04368
Publisher: MDPI AG
Date: 29-07-2022
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets—particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations.
Publisher: Elsevier
Date: 2023
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.JNS.2015.06.053
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper cortical and lower motor neurons. ALS causes death within 2-5years of diagnosis. Diet and body mass index influence the clinical course of disease, however there is limited information about the expression of metabolic proteins and fat-derived cytokines (adipokines) in ALS. In healthy controls and subjects with ALS, we have measured levels of proteins and adipokines that influence metabolism. We find altered levels of active ghrelin, gastric inhibitory peptide (GIP), pancreatic polypeptide (PP), lipocalin-2, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and 8 (IL-8), and tumor necrosis factor alpha (TNFα) in the plasma of ALS patients relative to controls. We also observe a positive correlation between the expression of plasma nerve growth factor (NGF) relative to disease duration, and an inverse correlation between plasma glucagon and the ALS functional rating scale-revised (ALSFRS-R). Further studies are required to determine whether altered expression of metabolic proteins and adipokines contribute to motor neuron vulnerability and how these factors act to modify the course of disease.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2022
DOI: 10.1186/S40478-022-01360-5
Abstract: A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin ( n -agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n -agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n -agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n -agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
DOI: 10.1186/S13059-021-02275-5
Abstract: People with neurodegenerative disorders show erse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
Publisher: Springer US
Date: 16-10-2022
Publisher: BMJ
Date: 29-04-2018
Abstract: To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival. Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment. Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4 p .01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7) p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (−0.68 points/month vs −0.39 points/month p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03). Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.
Location: Australia
Location: Australia
Start Date: 2012
End Date: 2015
Funder: Queensland Government
View Funded ActivityStart Date: 2012
End Date: 2012
Funder: Australian Academy of Science
View Funded ActivityStart Date: 2015
End Date: 2015
Funder: University of Queensland
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Motor Neurone Disease Research Institute of Australia
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Royal Brisbane and Women's Hospital Foundation
View Funded ActivityStart Date: 2020
End Date: 2023
Funder: FightMND
View Funded ActivityStart Date: 2020
End Date: 2022
Funder: National Health and Medical Research Council
View Funded Activity