A5026042960- Parkinson's Disease Mechanisms and Treatments
- Amyotrophic Lateral Sclerosis Research
- Nerve injury and regeneration
- Nuclear Receptors and Signaling
- Alzheimer's disease research and treatments
- RNA Research and Splicing
- Neurogenetic and Muscular Disorders Research
- Neurological disorders and treatments
- Cellular transport and secretion
- Neurological diseases and metabolism
- Genetic Neurodegenerative Diseases
- Cholinesterase and Neurodegenerative Diseases
- Protein Kinase Regulation and GTPase Signaling
- Cellular Mechanics and Interactions
- Neurogenesis and neuroplasticity mechanisms
- RNA regulation and disease
- Cell Adhesion Molecules Research
- Cancer-related gene regulation
- Neuroscience and Neuropharmacology Research
- Ubiquitin and proteasome pathways
- Muscle Physiology and Disorders
- Endoplasmic Reticulum Stress and Disease
- Prion Diseases and Protein Misfolding
- Autism Spectrum Disorder Research
- Botulinum Toxin and Related Neurological Disorders
Cardiff University
2015-2025
Belgorod National Research University
2021-2024
Institute of Physiologically Active Compounds
2009-2021
Russian Academy of Sciences
2011-2015
Moscow Region State University
2013
University of Sheffield
2013
Tel Aviv Sourasky Medical Center
2011
Tel Aviv University
2011
University of Edinburgh
2001-2008
Institute of Gene Biology
2000-2005
Presynaptic nerve terminals release neurotransmitters repeatedly, often at high frequency, and in relative isolation from neuronal cell bodies. Repeated requires cycles of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly disassembly, with continuous generation reactive SNARE-protein intermediates. Although many forms neurodegeneration initiate presynaptically, only few pathogenic mechanisms are known, the functions presynaptic proteins linked to...
Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein. α-Synuclein has been the focus intense attention since mutations in it were identified as cause for familial Parkinson's disease. Despite their disease relevance, normal physiological function synucleins remained elusive. To address this, we generated characterized αβγ-synuclein knockout mice, which lack all members this protein family. Deletion...
Misfolded α-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about physiological role for native, unfolded limited. Using brains mice lacking α-, β-, and γ-synuclein, we report that extracellular monomeric enters neurons localizes to mitochondria, interacts with ATP synthase subunit α, modulates function. combination biochemical, live-cell imaging mitochondrial respiration analysis, found brain mitochondria γ-synuclein knock-out are uncoupled, as...
To investigate if different neurotrophins regulate the survival of neurons at successive developmental stages, we studied effect nerve growth factor (NGF), brain-derived neurotrophic (BDNF) and neurotrophin-3 (NT-3) on mouse trigeminal closely staged intervals in development. We show that during earliest stages target field innervation display a transitory response to BDNF NT-3. This is lost as become NGF-dependent shortly before neuronal death begins ganglion. NT-3 mRNAs are expressed...
Optic nerve head (ONH) astrocytes have been proposed to play both protective and deleterious roles in glaucoma. We now show that, within the postlaminar ONH myelination transition zone (MTZ), there are that normally express Mac-2 (also known as Lgals3 or galectin-3), a gene typically expressed only phagocytic cells. Surprisingly, even healthy mice, MTZ other constitutive internalize large axonal evulsions contain whole organelles. In mouse glaucoma models, further up-regulate expression....
The synucleins (α, β, and γ) are highly homologous proteins thought to play a role in regulating neurotransmission found abundantly presynaptic terminals. To overcome functional overlap between synuclein understand their signaling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the family. effect on system was assessed adult (4- 14-month-old) animals using combination behavioral, biochemical, histological, electrochemical techniques. Adult...
Abstract Neurodegeneration in Parkinson’s disease (PD) is accompanied by a local immune reaction the affected brain regions. It well established that α‐synuclein directly implicated pathogenesis of PD. Development often associated with changes expression and cellular compartmentalisation this protein; moreover, its oligomers or protofibrils are released to CSF plasma patients. Aggregated can trigger activation microglia; however, capacity induce production specific autoantibodies (AAb) has...
Abstract Alpha‐synuclein is intimately involved in the pathogenesis of Parkinson's disease, and has been implicated regulation synthesis, release reuptake dopamine (DA). However, mice lacking members synuclein family have reported to display no overt behavioural phenotype. This may be a result compensatory upregulation other synucleins during development. Here we report on behaviour DA synapse function alpha‐synuclein null, gamma‐synuclein alpha‐gamma‐synuclein double‐null knockout mice....
Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). Mutant is known to confer cytoplasmic gain of function but its effects nucleus are less understood. an essential component paraspeckles, subnuclear bodies assembled on a lncRNA NEAT1. Paraspeckles may play protective role specifically degenerating spinal motor neurons. However it still unknown how endogenous levels mutant would affect NEAT1/paraspeckles. Using novel cell lines with modified by CRISPR/Cas9 and human...
Paraspeckles are nuclear bodies formed by a set of specialized proteins assembled on the long non-coding RNA NEAT1; they have role in retention hyperedited transcripts and associated with response to cellular stress. Fused sarcoma (FUS) protein, linked number neurodegenerative disorders, is an essential paraspeckle component. We shown that its recruitment these structures mediated N-terminal region requires prion-like activity. FUS interacts p54nrb/NONO, major constituent paraspeckles,...
Dysfunction of two structurally and functionally related proteins, FUS TAR DNA-binding protein 43 kDa (TDP-43), implicated in crucial steps cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone form non-amyloid inclusions the affected nervous tissues, but role these proteinaceous aggregates disease onset progression is still uncertain. To address this question, we designed a variant FUS,...
Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, overexpression does not trigger formation fibrillar LB-like mice. We hypothesized that interactions between exogenous and endogenous mouse synuclein homologs could be attenuating fibrillization mice, therefore, we systematically...
Paraspeckles are subnuclear bodies assembled on a long non-coding RNA (lncRNA) NEAT1. Their enhanced formation in spinal neurons of sporadic amyotrophic lateral sclerosis (ALS) patients has been reported but underlying mechanisms unknown. The majority ALS cases characterized by TDP-43 proteinopathy. In current study we aimed to establish whether and how pathology may augment paraspeckle assembly. Paraspeckle human samples was analysed RNA-FISH laser capture microdissection followed qRT-PCR....
α-Synuclein is a major protein constituent of Lewy bodies and mutations in α-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation perikaryal neuritic aggregates α-synuclein, which presynaptic protein, that disrupt transport lead to its proximal accumulation. We found mutant forms either associated with disease (A30P or A53T) mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal following transfection into...
The synucleins are a unique family of small intracellular proteins that have recently attracted considerable attention because their involvement in human neurodegenerative diseases. We cloned new member the synuclein called persyn. In contrast to other synucleins, which presynaptic CNS neurons, persyn is cytosolic protein expressed predominantly cell bodies and axons primary sensory sympathetic motoneurons. Northern blotting, situ hybridization, Western immunohistochemistry revealed mRNA...
Abstract The molecular and cellular mechanisms underlying neuronal loss in neurodegenerative diseases are unclear. It is generally thought that aggregation of mutated, abnormally modified or folded proteins leads to the accumulation extracellular, intracellular intranuclear deposits severely compromise cell physiology, leading death affected neurons. However, there growing evidence apoptosis absence obvious pathological could have a serious impact on pathogenesis diseases. α‐Synuclein has...
Abstract The growing body of evidence suggests that intermediate products α‐synuclein aggregation cause death sensitive populations neurones, particularly dopaminergic which is a critical event in the development Parkinson's disease and other synucleinopathies. role two members family, β‐synuclein γ‐synuclein, neurodegeneration less understood. We studied effect inactivation γ‐ synuclein gene on mouse midbrain neurones. Reduced number neurones was found substantia nigra pars compacta (SNpc)...