A5033720368- Parkinson's Disease Mechanisms and Treatments
- Amyotrophic Lateral Sclerosis Research
- CRISPR and Genetic Engineering
- Alzheimer's disease research and treatments
- Monoclonal and Polyclonal Antibodies Research
- Genetic Neurodegenerative Diseases
- Cellular transport and secretion
- Pluripotent Stem Cells Research
- Lysosomal Storage Disorders Research
- Nuclear Receptors and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Autophagy in Disease and Therapy
- Nerve injury and regeneration
- Neurogenetic and Muscular Disorders Research
- Enzyme Structure and Function
- Amino Acid Enzymes and Metabolism
- Signaling Pathways in Disease
- Protein Degradation and Inhibitors
- Adenosine and Purinergic Signaling
- Peptidase Inhibition and Analysis
- Neurological disorders and treatments
- Polyamine Metabolism and Applications
- Autism Spectrum Disorder Research
- Immune cells in cancer
Montreal Neurological Institute and Hospital
2021-2025
McGill University
2021-2025
Structural Genomics Consortium
2022
Concordia University
2016
Hebrew University of Jerusalem
2007
TBK1 is a serine-threonine protein kinase that has been linked to number of diseases including amyotrophic lateral sclerosis and frontotemporal dementia. Reproducible research on hampered by the lack well characterized antibodies. In this study, we 11 commercial antibodies for use in immunoblot, immunofluorescence immunoprecipitation, using an isogeneic knock-out cell line as control. We identify appear specific all three applications but invite readers interpret present findings based their...
The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson's disease (PD) and other synucleinopathies; however, the mechanisms underlying internalization cellular are enigmatic. Here, we use confocal superresolution microscopy, subcellular fractionation, electron microscopy (EM) immunogold-labeled α-synuclein preformed (PFFs) demonstrate that this form protein undergoes rapid targeted directly lysosomes in as little 2 min. Uptake PFFs disrupted by macropinocytic...
<ns3:p>Sequestosome-1, encoded by the gene <ns3:italic>SQSTM1</ns3:italic>, functions as a bridge between ubiquitinated proteins and proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal disorders (FTD). reproducible research would be facilitated with availability well-characterized anti-Sequestosome-1...
Abstract Background Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function health and disease. Yet, since differentiation survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use study dysfunction associated with pathogenic defects CSF1R. Methods Serial modifications existing protocol were made, including but not limited changes growth combination drive differentiation,...
Abstract Despite known sex differences in human synucleinopathies such as Parkinson’s disease, the impact of on alpha-synuclein pathology mouse models has been largely overlooked. To address this need, we examine whole brain signatures neurodegeneration due to aSyn toxicity M83 model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 μm 3 isotropic voxel; -7, 30, 90 and 120 days post-injection [dpi]; n ≥ 8 mice/group/sex/time point). initiate spreading, mice are inoculated...
Abstract The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) Dementia with Lewy bodies (DLB). Molecular chaperones play important roles diseases members of the chaperone machinery are often deposited bodies. Here, we show that Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, co-deposited Hsp70 insoluble fractions two mouse models misfolding. also co-localized...
<ns3:p>Sequestosome-1, encoded by the gene <ns3:italic>SQSTM1</ns3:italic>, functions as a bridge between ubiquitinated proteins and proteasome or autophagosome, thereby regulating protein degradation pathways. Loss of Sequestosome-1 is hypothesized to enhance neurodegeneration progression in several diseases, including amyotrophic lateral sclerosis (ALS) frontotemporal disorders (FTD). reproducible research would be facilitated with availability well-characterized anti-Sequestosome-1...
Mer tyrosine kinase (MerTK) is a receptor that mediates non-inflammatory, homeostatic phagocytosis of diverse types cellular debris. Highly expressed on the surface microglial cells, MerTK importance in brain development, homeostasis, plasticity and disease. Yet, involvement this clearance protein aggregates accumulate with ageing neurodegenerative diseases has yet to be defined. The current study explored function uptake alpha-synuclein fibrils which play causative role pathobiology...
Synucleinopathies form a group of neurodegenerative diseases defined by the misfolding and aggregation α-synuclein (α-syn). Abnormal accumulation spreading α-syn aggregates lead to synapse dysfunction neuronal cell death. Yet, little is known about synaptic mechanisms underlying pathology. Here we identified β-isoforms neurexins (β-NRXs) as presynaptic organizing proteins that interact with preformed fibrils (α-syn PFFs), toxic aggregates, but not monomers. Our surface protein binding assays...
Autosomal recessive mutations in either PRKN or PINK1 are associated with early-onset Parkinson's disease. The corresponding proteins, PRKN, an E3 ubiquitin ligase, and the mitochondrial serine/threonine-protein kinase play a role quality control. Using CRISPR/CAS9 technology we generated three human iPSC lines from well characterized AIW002-02 control line. These isogenic iPSCs contain homozygous knockouts of (PRKN-KO, CBIGi001-A-1), (PINK1-KO, CBIGi001-A-2) both (PINK1-KO/PRKN-KO,...
Abstract The USP19 deubiquitinase is found in a locus associated with Parkinson’s Disease (PD), interacts chaperonins, and promotes secretion of α-synuclein (α-syn) through the misfolding-associated protein (MAPS) pathway. Since these processes might modulate processing α-syn aggregates PD, we inactivated (KO) mice expressing A53T mutation whom preformed fibrils (PFF) had been injected striatum. Compared to WT, KO brains showed decreased accumulation phospho-synuclein (pSyn) positive...
In the central nervous system, glutamate transporters terminate actions of this neurotransmitter by concentrating it into cells surrounding synapse a process involving sodium and proton cotransport followed countertransport potassium. These contain two oppositely oriented helical hairpins 1 2. Hairpin originates from cytoplasm, but its tip is close to that hairpin 2, which enters transporter9s lumen extracellular side. Here we address question whether and/or domains undergo conformational...
Abstract Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in prion‐like manner contributing to disease progression Parkinson's (PD) and other synucleinopathies. In fact, timed inoculation M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading pathogenic alpha‐synuclein, as detected by markers for the phosphorylation S129 aSyn. However, whether...
SUMMARY Lewy bodies (LBs), rich in α-synuclein, are a hallmark of Parkinson’s disease (PD). Understanding their biogenesis is likely to provide insight into the pathophysiology PD, yet cellular model for LB formation remains elusive. The realization that immune challenge trigger neurodegenerative diseases has been breakthrough understanding PD. Here, iPSC-derived human dopaminergic (DA) neurons from multiple healthy donors were found form LB-like inclusions following treatment with α-...
The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), responsible for hydrolysis of glucocerebroside to glucose and ceramide. Heterozygous mutations have been associated with development Parkinson's disease (PD) dementia Lewy bodies (DLB). We generated two induced pluripotent stem cell (iPSC) lines from PD patients carrying heterozygous W378G or N370S subsequently produced isogenic control using CRISPR/Cas9 genome editing. patient-derived iPSCs maintained full pluripotency,...
<ns3:p>VAPB is an adaptor protein known for its role as anchor other proteins at the endoplasmic reticulum. A mutant form of VAPB has been linked to amyotrophic lateral sclerosis and underlying mechanisms resulting from this defect are studied by researchers in area uncover implication disease. Here we have characterized six commercial antibodies western blot, immunoprecipitation, immunofluorescence using a standardized experimental protocol based on comparing read-outs knockout cell lines...
Abstract Amyotrophic lateral sclerosis (ALS) represents a complex neurodegenerative disorder with significant genetic heterogeneity. To date, both the etiology and underlying molecular mechanisms driving this disease remain poorly understood, although in recent years number of studies have highlighted mutations causative for ALS. With these pointing to potential pathways that may be affected within individuals ALS, having ability generate human neurons other relevant cells containing becomes...
Abstract Alpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences age onset, prevalence and disease presentation synucleinopathies, impact on aSyn propagation received very little attention. To address this need, we examined whole brain signatures neurodegeneration due to toxicity M83 model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 μm 3 isotropic voxel; acquired −7, 30, 90 120...
Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons from substantia nigra. Affected exhibit intracellular aggregates primarily composed misfolded and phosphorylated alpha-synuclein (aSyn). In pathological conditions, this presynaptic protein has been shown to be transmitted cell in prion-like manner, which contributes progression disease. Single-chain variable fragments (scFvs) are small polypeptides derived binding domains...
Abstract Synucleinopathies form a group of neurodegenerative diseases defined by misfolding and aggregation alpha-synuclein (α-syn). Abnormal accumulation spreading α-syn aggregates lead to synapse dysfunction neuronal cell death. Yet, little is known about synaptic mechanisms underlying pathology. Here we identified β-isoforms neurexins (β-NRXs) as presynaptic organizing proteins that interact with preformed fibrils (α-syn PFFs), toxic aggregates, but not monomers. Our surface protein...
Abstract MerTK is a receptor tyrosine kinase that mediates the immunologically silent phagocytic uptake of diverse types cellular debris. Highly expressed on surface microglial cell, importance in brain development, homeostasis, plasticity, and disease. Yet, involvement this clearance protein aggregates accumulate with aging neurodegenerative diseases has yet to be defined. The current study explored function alpha-synuclein fibrils which play causative role pathobiology synucleinopathies....