A5022636438- Cellular Mechanics and Interactions
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Cardiomyopathy and Myosin Studies
- Cell Image Analysis Techniques
- Neuroscience and Neuropharmacology Research
- Cellular transport and secretion
- Microtubule and mitosis dynamics
- RNA Interference and Gene Delivery
- Amyotrophic Lateral Sclerosis Research
- Muscle Physiology and Disorders
- Biochemical and Structural Characterization
- Supramolecular Self-Assembly in Materials
- Inflammasome and immune disorders
- Nicotinic Acetylcholine Receptors Study
- Axon Guidance and Neuronal Signaling
- Signaling Pathways in Disease
- Endoplasmic Reticulum Stress and Disease
- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- Toxin Mechanisms and Immunotoxins
- Neurogenetic and Muscular Disorders Research
- Nerve injury and regeneration
- Neurogenesis and neuroplasticity mechanisms
- Ubiquitin and proteasome pathways
Macquarie University
2019-2024
UNSW Sydney
2016-2020
Abstract Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau −/− ) mice are profoundly protected from excitotoxic and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, this protection is due site-specific inhibition glutamate-induced Ras/ERK-mediated toxicity accumulation Ras-inhibiting SynGAP1, which...
Abstract Frontotemporal dementia and amyotrophic lateral sclerosis are clinically pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 genome-wide significant linkage in large European Australian family autosomal dominant inheritance of frontotemporal no mutation known or genes. Here we demonstrate the segregation novel missense variant CYLD (c.2155A>G, p.M719V) within region as cause this family....
Tropomyosins (Tpm) are master regulators of actin dynamics through forming co-polymers with filamentous actin. Despite the well-understood function muscle Tpms in contractile apparatus cells, much less is known about diverse physiological cytoplasmic eukaryotic cells. Here, we investigated role Tpm4.2 isoform neuronal processes including signaling, neurite outgrowth and receptor recycling using primary neurons from knock-out mice. Live imaging calcium electrophysiology data demonstrated...
Abstract Sphingosine 1‐phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein‐coupled receptors, S1PR1‐S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) potent S1P receptor agonist causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties FTY720 in several neurodegenerative paradigms; however, the native ligand have not been established. We aimed establish significance...
The axon initial segment (AIS) is the site of action potential initiation and serves as a cargo transport filter diffusion barrier that helps maintain neuronal polarity. AIS actin cytoskeleton comprises patches periodic sub-membranous rings. We demonstrate tropomyosin isoform Tpm3.1 co-localizes with inhibition led to reduction in density patches. Furthermore, showed distribution similar rings but was only partially congruent Nevertheless, affected uniformity periodicity reduced accumulation...
The recently diagnosed leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement Leg spasticity (HBSL) is caused by mutations of the cytoplasmic aspartyl-tRNA synthetase geneDARS. physiological role DARS in translation to accurately pair aspartate its cognate tRNA. Clinically, HBSL subjects show a distinct pattern hypomyelination develop progressive leg spasticity, variable cognitive impairment epilepsy. To elucidate underlying pathomechanism, we comprehensively assessed...
The axon initial segment (AIS) is located at the proximal demarcating boundary between axonal and somatodendritic compartments. AIS facilitates generation of action potentials maintenance neuronal polarity. In this study, we show that location assembly, as marked by Ankyrin G, corresponds to nodal plane lowest-order harmonic Laplace-Beltrami operator solved over shape. This correlation establishes a coupling assembly cell morphology. We validate for neurons with atypical morphology...
The culturing of primary neurons represents a central pillar neuroscience research. Primary are derived directly from brain tissue and recapitulate key aspects neuronal development in an vitro setting. Unlike neural stem cells, do not divide; thus, initial attachment cells to suitable substrate is critical. Commonly used polylysine substrates can suffer batch variability owing their polymeric nature. Herein, we report the use chemically well-defined, self-assembling tetrapeptides as for...
Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress Alzheimer's disease (AD) other tauopathies. This requires the release of tau from donor cells, but underlying molecular mechanisms remained unknown. Here, we established interactome C-terminal tail region identified syntaxin 8 (STX8) a mediator cells. Similarly, showed 6 (STX6), part same SNARE family STX8 also facilitated release. STX6 was previously genetically linked...
Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein–protein interactions (PPIs).
There are many unanswered questions about the roles of actin pointed end capping and nucleation by tropomodulins (Tmod) in regulating neural morphology. Previous studies indicate that Tmod1 Tmod2 regulate morphology dendritic arbor spines. Tmod3, which is expressed brain, had only a minor influence on Although these established defined role Tmod synaptic morphology, mechanisms Tmods exert effects unknown. Here, we overexpressed series mutated forms with disrupted actin-binding sites...
Nerve cell connections, formed in the developing brain of mammals, undergo a well-programmed process maturation with changes their molecular composition over time. The major structural element at post-synaptic specialization is actin cytoskeleton, which composed different populations functionally distinct filaments. Previous studies, using ultrastructural and light imaging techniques have established presence filament site. However, it remains unknown, how these are defined In present study,...
Genetically encoded filamentous actin probes, Lifeact, Utrophin and F-tractin, are used as tools to label the cytoskeleton. Recent evidence in several different cell types indicates that these probes can cause changes dynamics, altering morphology function. Although commonly visualise dynamics neurons, their effects on axonal dendritic has not been systematically characterised. In this study, we quantitatively analysed effect of F-tractin neuronal morphogenesis primary hippocampal neurons....
The mobility of hydrophobic moieties at a peptide nanofibre surface determines its suitability as scaffold for sensitive primary cells.
Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the isoform Tpm3.1 controlling changes size neuronal growth cones neurite growth. Here, we used primary mouse hippocampal neurons C57/Bl6 wild type Bl6Tpm3flox transgenic mice carry out morphometric analyses response absence products, well investigate effect C-terminal truncation on ability modulate morphogenesis. We found that knock-out leads...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as cause of familial ALS (fALS) 2012. We investigated the functional impact mutant expression spinal cords during mouse development. developed novel model C71G under control Hb9 promoter, targeting to α-motor neurons cord Embryos transgenic mice showed evidence significant reduction brachial nerve diameter loss Mendelian inheritance....
Tropomyosins, a family of actin-associated proteins, bestow actin filaments with distinct biochemical and physical properties which are important for determining cell shape regulating many cellular processes in eukaryotic cells. Here, we used RNA-seq to investigate the effect four tropomyosin isoforms on gene expression undifferentiated differentiated rat B35 neuroblastoma In cells, overexpression Tpm1.12, Tpm2.1, Tpm3.1, Tpm4.2 differentially regulates vast number genes, clustering into...
ABSTRACT The axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about specialized structural complex in AIS. While an intact actin cytoskeleton required for AIS formation, pharmacological disruption polymerization compromises vesicle but does not affect overall structure. In this study, we found tropomyosin isoform Tpm3.1 decorates population...
Cyclotides are naturally occurring cyclic peptides with three disulfide bonds, offering remarkable stability. In neurological disorders, the formation of a complex between postsynaptic density protein 95 and NMDA receptors (NMDARs) can lead to neuronal cell death. this study, we modified MCoTI-II cyclotide backbone polyarginines for enhanced intracellular delivery grafted 9-amino acid PSD-95-NMDAR inhibitor sequence, NR2B9c, into loop 6. We found that incorporating significantly improved...
The axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about specialized structural complex in AIS. While an intact actin cytoskeleton required for AIS formation, pharmacological disruption polymerization compromises vesicle but does not affect overall structure. In this study, we found tropomyosin isoform Tpm3.1 decorates population relatively...
Tropomyosin (Tpm) has been regarded as the master regulator of actin dynamics. Tpms regulate binding various proteins involved in restructuring actin. The cytoskeleton is predominant cytoskeletal structure dendritic spines. Its regulation critical for spine formation and long-term activity-dependent changes synaptic strength. Tpm isoform Tpm3.1 enriched spines, but its role regulating synapse function not known. To determine Tpm3.1, we studied cultured hippocampal neurons from transgenic...