A5063050678- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Alzheimer's disease research and treatments
- Clusterin in disease pathology
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Genetic Neurodegenerative Diseases
- Neurological diseases and metabolism
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Autophagy in Disease and Therapy
- Neuroinflammation and Neurodegeneration Mechanisms
- Adenosine and Purinergic Signaling
- Ubiquitin and proteasome pathways
- biodegradable polymer synthesis and properties
- Cholinesterase and Neurodegenerative Diseases
- Nuclear Structure and Function
- Mass Spectrometry Techniques and Applications
- Protein Structure and Dynamics
- Histone Deacetylase Inhibitors Research
- Metabolomics and Mass Spectrometry Studies
- Cell death mechanisms and regulation
- Genetics and Neurodevelopmental Disorders
- Computational Drug Discovery Methods
- Erythrocyte Function and Pathophysiology
Illawarra Health and Medical Research Institute
2016-2025
University of Wollongong
2016-2025
Christie's
2022
Sustainable Horizons Institute
2019
University of Cambridge
2009-2010
Centenary Institute
2005
The University of Sydney
2005
Significance Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) to a form inside living cells in prion-like fashion. We now report WT be transmitted from cell cell, propagated protein perpetuated. Misfolded transmission between mediated through release uptake aggregates or via small membrane-bounded...
Clusterin is an extracellular chaperone present in all disease-associated amyloid deposits, but its roles formation and protein deposition vivo are poorly understood. The current study initially aimed to characterize the effects of clusterin on vitro by a panel eight substrates. Two substrates (Alzheimer's beta peptide PI3-SH3 domain) were then used further experiments examine cytotoxicity probe mechanism action. We show that exerts potent formation, nature extent which vary greatly with...
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of TDP-43 is a major component, characteristic pathological feature most ALS FTD patients. Here we use genome-wide linkage analysis large ALS/FTD kindred to identify novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified CCNF missense mutation...
Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such β-amyloid and α-synuclein trigger microglial activation, leading caspase-1 IL-1β secretion. Both contribute disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting role for NLRP3. Prior studies, however, suggested mice microglia do not express NLRP3, generated independent Here, we demonstrate...
Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation promote activation neuroprotective microglia mouse models ALS. To our knowledge, association host Treg expansion with ALS has not been studied vivo.To assess role Tregs regulating pathophysiology humans outcome increasing activity...
The discovery that prion protein can misfold into a pathological conformation encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding neurodegenerative disease. Many diseases with misfolding component are now classified as "prion-like" owing to the symptoms aggregation pathology in affected individuals. neuromuscular disorder amyotrophic lateral sclerosis (ALS) is characterized by inclusions formed either TAR...
Abstract Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease associated with protein misfolding and aggregation. Most cases are characterized by TDP-43 positive inclusions, while minority of familial ALS instead FUS SOD1 respectively. Cells can generate inclusions variable type including previously aggresomes, IPOD or JUNQ structures depending on the misfolded protein. invariably forms but it remains unclear whether other aggregates arise as one these described...
Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute pathogenicity a reduced ability complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers characteristic large insoluble aggregates within motor system cells. Here we report that...
Significance Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with wide clinical variability and complex pathogenesis. One of the hallmarks ALS presence diverse inclusions formed by apparently disparate misfolded proteins, which are unrelated in sequence, structure, function, localization. Many these addition, not usual interaction partners primary inclusion-forming ALS-related proteins (SOD1, TDP-43, FUS). Here, we show that common feature coaggregating their...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the rapid and progressive degeneration of upper lower motor neurons in spinal cord, brain stem cortex. The first gene linked to ALS was encoding free radical scavenging enzyme superoxide dismutase-1 (SOD1) that currently has over 180, mostly missense, ALS-associated mutations identified. SOD1-associated fALS patients show remarkably broad mean survival times (< 1 year ~17 years death post-diagnosis) are...
Abstract Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting voluntary muscle movement as well cognitive and other behavioural domains at later stages. No effective treatment for ALS currently available. Elevated neuroinflammation, oxidative stress alterations to the endocannabinoid system are evident in ALS. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory anti-oxidant properties. Thus, we evaluated remedial effects of chronic oral...
Abstract A large body of literature suggests that amyotrophic lateral sclerosis (ALS) pathology is intimately linked with neuroinflammation, specifically activation and recruitment microglia astrocytes. The actual cause gliosis unclear. Extracellular Cu/Zn superoxide dismutase (SOD1) has recently been shown to activate in a CD14 dependant mechanism providing one potential pathway by which glial cells become activated. As protein inclusions are thought be an important part ALS associated all...
The P2X7 purinergic receptor is a ligand-gated cation channel expressed on leukocytes including microglia. This study aimed to determine if activation induces the uptake of organic cations, reactive oxygen species (ROS) formation, and death in murine microglial EOC13 cell line. Using macrophage J774 line as positive control, RT-PCR, immunoblotting, immunolabelling established presence cells. A cytofluorometric assay demonstrated that agonists adenosine-5′-triphosphate (ATP)...
Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed progressive spread pathology that has been likened to transmission infectious prions. Cell-to-cell SOD1 protein aggregates dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain be elucidated. We demonstrate in this paper interact with cell surface triggering activation Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis....
Transactivating DNA-binding protein-43 (TDP-43) deposits represent a typical finding in almost all ALS patients, more than half of FTLD patients and with several other neurodegenerative disorders. It appears that perturbation nucleo-cytoplasmic transport is an important event these conditions but the mechanistic role fate TDP-43 during neuronal degeneration remain elusive. We have developed experimental system for visualising perturbed nucleocytoplasmic at single-cell level vivo using...