A5021476193- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Zebrafish Biomedical Research Applications
- Genetic Neurodegenerative Diseases
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Nerve injury and regeneration
- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- Congenital heart defects research
- RNA Research and Splicing
- Developmental Biology and Gene Regulation
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Alzheimer's disease research and treatments
- Neurogenesis and neuroplasticity mechanisms
- Photoreceptor and optogenetics research
- Neuroscience and Neural Engineering
- Aquaculture disease management and microbiota
- Parkinson's Disease Mechanisms and Treatments
- Ion Channels and Receptors
- Cystic Fibrosis Research Advances
- Biomimetic flight and propulsion mechanisms
- Advanced Fluorescence Microscopy Techniques
- Fish Ecology and Management Studies
Macquarie University
2014-2024
The University of Sydney
2011-2016
Robert Bosch (Australia)
2011-2014
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...
Microglia are specialized phagocytes in the vertebrate central nervous system (CNS). As resident immune cells of CNS they play an important role removal dying neurons during both development and several neuronal pathologies. have been shown to prevent diffusion damaging degradation products by engulfment ingestion. Here we describe a live imaging approach that uses UV laser ablation selectively stress kill spinal visualize clearance remnants microglia zebrafish cord. In vivo confirmed motile...
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...
Currently there is a lack in fundamental understanding of disease progression most neurodegenerative diseases, and, therefore, treatments and preventative measures are limited. Consequently, great need for adaptable, yet robust model systems to both investigate elementary mechanisms discover effective therapeutics. We have generated Tol2 Gateway-compatible toolbox study disorders zebrafish, which includes promoters astrocytes, microglia motor neurons, multiple fluorophores, compatibility the...
Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark neurodegenerative diseases including Amyotrophic Lateral Sclerosis. localizes predominantly in nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter condensation properties TDP-43, contributing to transition liquid-like biomolecular solid-like aggregates. However, date it has been challenge study...
Abstract Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of trinucleotide repeat region within ATXN3/MJD gene. Mutation ATXN3 causes formation ataxin‐3 protein aggregates, neurodegeneration, and motor deficits. Here we investigated therapeutic potential mechanistic activity sodium butyrate (SB), salt butyric acid, metabolite naturally produced gut microbiota, on cultured SH‐SY5Y cells transgenic zebrafish...
Locomotor strategies in terrestrial tetrapods have evolved from the utilisation of sinusoidal contractions axial musculature, evident ancestral fish species, to reliance on powerful and complex limb muscles provide propulsive force. Within tetrapods, a hindlimb-dominant locomotor strategy predominates, its evolution is considered critical for success tetrapod transition onto land. Here, we determine developmental mechanisms pelvic fin muscle formation living species at points within...
Generation of reactive oxygen species (ROS) has been shown to be important for many physiological processes, ranging from cell differentiation apoptosis. With the development genetically encoded photosensitiser KillerRed (KR) it is now possible efficiently produce ROS dose-dependently in a specific type upon green light illumination. Zebrafish are ideal vertebrate animal model these optogenetic methods because their transparency and efficient transgenesis. Here we describe zebrafish that...
The spatial and temporal regulation of calcium signaling in neuronal growth cones is essential for axon guidance. In cones, the endoplasmic reticulum (ER) a significant source signals. However, it not clear whether ER remodeled during motile events to localize signals steering cones. expression ER-calcium sensor, stromal interacting molecule 1 (STIM1) necessary cone toward calcium-dependent guidance cue BDNF, with STIM1 functioning sustain through store-operated entry. also required away...
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterised by the death of upper and lower motor neurons. Approximately 10% cases have known family history ALS disease-linked mutations in multiple genes been identified. ALS-linked CCNF were recently reported, however pathogenic mechanisms associated with these are yet to be established. To investigate possible mechanisms, we developed vitro vivo models based on an missense mutation CCNF....
FUS mutations can occur in familial amyotrophic lateral sclerosis (fALS), a neurodegenerative disease with cytoplasmic inclusion bodies motor neurons. To investigate pathology, we generated transgenic zebrafish expressing GFP-tagged wild-type or fALS (R521C) human FUS. Cell cultures were made from these and the subcellular localization of generation stress granule (SG) inclusions examined different cell types, including differentiated We demonstrate that mutant is mislocalized nucleus to...
Pathological forms of TAR DNA-binding protein 43 (TDP-43) are present in almost all cases amyotrophic lateral sclerosis (ALS), and 20% familial ALS due to mutations superoxide dismutase 1 (SOD1). Redox regulation is critical maintain cellular homeostasis, although how this relates unclear. Here, we demonstrate that the redox function disulfide isomerase (PDI) protective against misfolding, cytoplasmic mislocalization TDP-43, ER stress, ER-Golgi transport dysfunction, apoptosis neuronal cells...
ABSTRACT Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using hybrid positional cloning and next generation sequencing approach, identified mutations the nuclear localisation signal (NLS) T-box transcription factor 4 (Tbx4) impair protein, resulting altered gene expression patterns during development failure development....
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that characterized by progressive weakness, paralysis and muscle loss often resulting in patient death within 3–5 years of diagnosis. Recently, we identified disease-linked mutations the CCNF gene, which encodes cyclin F protein, cohorts patients with familial sporadic ALS frontotemporal dementia (FTD) (Williams KL et al . 2016 Nat. Commun. 7 , 11253. ( doi:10.1038/ncomms11253 )). Cyclin part Skp1-Cul-F-box (SCF) E3...
Pseudomonas aeruginosa is a significant cause of mortality in patients with cystic fibrosis (CF). To explore the interaction CF isolate P. PASS1 innate immune response, we have used Danio rerio (zebrafish) as an infection model. Confocal laser scanning microscopy (CLSM) enabled visualization direct interactions between zebrafish macrophages and PASS1. Dual RNA-sequencing host-pathogen was undertaken to profile RNA expression simultaneously pathogen host during infection. Following...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. ALS can be modeled in zebrafish (Danio rerio) through the expression human ALS-causing genes, such as superoxide dismutase 1 (SOD1). Overexpression mutated SOD1 protein causes aberrant branching and shortening spinal axons. Despite this, functional relevance this axon morphology remains elusive. Our aim was to determine whether axonopathy correlated with impaired...
Using a standard confocal setup, UV ablation method can be utilized to selectively induce cellular injury and visualize single-cell responses cell-cell interactions in the CNS real-time. Previously, studying these cell-specific after often required complicated setups or transfer of cells animals into different, non-physiological environments, confounding immediate short-term analysis. For example, drug-mediated approaches lack specificity that is study interactions. Similarly, while...
The past decade has seen a rapid acceleration in the discovery of new genetic causes ALS, with more than 20 putative ALS-causing genes now cited. These encode proteins that cover diverse range molecular functions, including free radical scavenging (e.g., SOD1), regulation RNA homeostasis TDP-43 and FUS), protein degradation through ubiquitin-proteasome system ubiquilin-2 cyclin F) autophagy (TBK1 sequestosome-1/p62). It is likely various initial triggers disease (either genetic,...