A5056229630- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Extracellular vesicles in disease
- Cholinesterase and Neurodegenerative Diseases
- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Circular RNAs in diseases
- MicroRNA in disease regulation
- Prion Diseases and Protein Misfolding
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Cerebrospinal fluid and hydrocephalus
- Genetic Neurodegenerative Diseases
- Neonatal and fetal brain pathology
- Fetal and Pediatric Neurological Disorders
- Ubiquitin and proteasome pathways
- Biotin and Related Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- Mast cells and histamine
- Bioinformatics and Genomic Networks
- Computational Drug Discovery Methods
- ATP Synthase and ATPases Research
- Nicotinic Acetylcholine Receptors Study
Occupational Cancer Research Centre
2015-2025
University of Toronto
2016-2025
Sunnybrook Health Science Centre
2017-2020
Health Sciences Centre
2017-2020
Tongji University
2020
German Center for Neurodegenerative Diseases
2018
Mayo Clinic in Florida
2017
Discovery Centre
2015
Canada Research Chairs
2015
Clinical diagnosis of Alzheimer's disease (AD) prior to the age 65 years is classified as young-onset (YOAD), whereas after considered late-onset (LOAD). Although rare autosomal mutations more commonly associate with YOAD, most YOAD and LOAD cases are sporadic. share amyloid tau pathology, but many patients show increased severity rate progression. The current study examined microRNA (miRNA) expression profile from exosomes isolated cerebrospinal fluid (CSF) biomarker-confirmed AD. Results...
Antibodies are a key resource in biomedical research yet there no community-accepted standards to rigorously characterize their quality. Here we develop procedure validate pre-existing antibodies. Human cell lines with high expression of target, determined through proteomics database, modified CRISPR/Cas9 knockout (KO) the corresponding gene. Commercial antibodies against target purchased and tested by immunoblot comparing parental KO. Validated used definitively identify most highly...
Objective A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that causes a downregulation transcripts, suggesting haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts ; long form (C9‐L) short (C9‐S), their function(s) largely unknown owing lack specific antibodies. Methods...
Objective To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and sporadic FTD. Methods GENFI participants were either carriers a pathogenic mutation progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau at risk carrying because first-degree relative was known...
Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities East Africa. We report neuropathologic findings five fatal cases (13–18 years age at death) nodding from Acholi people northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving cerebral cortex, subcortical nuclei brainstem. There was preferential...
Abstract A hexanucleotide repeat expansion in a noncoding region of C9orf72 is the most common genetic cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reduction select or total transcript protein levels observed postmortem C9-ALS/FTD tissue, loss orthologues zebrafish C. elegans results motor deficits. However, how reduction ALS FTD might contribute to disease process remains poorly understood. It has been shown that interacts forms complex with SMCR8 WDR41,...
Amyotrophic lateral sclerosis (ALS) patients, includingC9orf72-carriers and identical twins [1], have highly variable disease characteristics (e.g., duration age/site of onset) [7], suggesting the influence epigenetic variations.DNA methylation (DNAm) is a key modification linked to risk several neurodegenerative diseases (Supplementary introduction).The cumulative assessment DNAm levels at age-related CpGs allows estimation multi-tissue age (epigenetic clock), which could be more accurate...
Abstract TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD). Cellular stress signalling granule dynamics are now recognized to play role ALS/FTD pathogenesis. Defective assembly associated with increased cellular vulnerability death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) critical factor. Here, we define...
Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal...
Abstract Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in rare, indicating that the progressive accumulation of exogenous factors – such as cellular stressors converge on play a key role disease pathogenesis. Post translational modifications SUMOylation essential roles response stressors. We therefore set out understand how may regulate health disease. find is regulated dynamically via When this process...
The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. high phenotypic heterogeneity patients includes a wide range age onset, modifiers which are largely unknown. Age onset could be influenced by environmental genetic factors both may trigger DNA methylation changes at CpG sites. We tested hypothesis that associated with some single nucleotide polymorphisms causing gain or loss sites thus resulting alterations....
Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include haploinsufficiency, G4C2/C4G2 RNA foci, dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, role of small expansions (e.g., 30-90 repeats) is unknown was investigated here.We conducted a molecular pathology study family in which father (unaffected at age 90) carried 70-repeat allele blood DNA that expanded to ≈1,750 repeats his children, causing...
Abstract Nodding syndrome is an enigmatic recurrent epidemic neurologic disease that affects children in East Africa. The illness begins with vertical nodding of the head and can progress to grand mal seizures death after several years. most recent outbreak occurred northern Uganda. We now describe clinicopathologic spectrum neuropathologic findings 16 or young adults fatal were correlated onset, duration progression their neurological illness. affected individuals ranged age from 14 25...
The understanding of how different cell types contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is limited. Here we generated a single-nucleus transcriptomic and epigenomic atlas the frontal cortex ALS cases with C9orf72 (C9) hexanucleotide repeat expansions sporadic (sALS). Our findings reveal shared pathways in C9-ALS sALS, characterized by synaptic dysfunction excitatory neurons disease-associated state microglia. disease subtypes diverge loss astrocyte homeostasis C9-ALS,...
Abstract Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in rare, indicating that exogenous factors – such as cellular stressors converge on play a key role disease pathogenesis. Post translational modifications SUMOylation essential roles response stressors. We therefore set out understand how may regulate health disease. find is regulated dynamically via When this process blocked vivo , we note age-dependent...
To present the postmortem neuropathologic report of a patient with CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.A 54-year-old man without significant medical history or family presented arm weakness, slowly progressed over 19 years to meet El Escorial criteria for clinically probable ALS bulbar and respiratory involvement, was found have p.R15L mutation. Postmortem examination took place including immunohistochemical staining CHCHD10, double...
Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immuno-stimulatory or damaged unknown. Here, we show in pre-symptomatic ALS-FTD patient cells brains cause...
Rigorously characterized antibodies are a key resource in biomedical research, yet there no community-accepted processes to characterize the quality of research grade antibodies. This has led proliferation poorly suspect quality, which turn flaws literature that hamper progress, including study human disease. We selected protein C9ORF72 as test case implement more standardized antibody characterization process. Mutations gene major genetic cause amyotrophic lateral sclerosis and...