A5059779856- Neuroinflammation and Neurodegeneration Mechanisms
- Amyotrophic Lateral Sclerosis Research
- Alzheimer's disease research and treatments
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- RNA Research and Splicing
- Neurogenetic and Muscular Disorders Research
- Mitochondrial Function and Pathology
- Genetic Neurodegenerative Diseases
- Parkinson's Disease Mechanisms and Treatments
- Genetics and Neurodevelopmental Disorders
- Genetics, Aging, and Longevity in Model Organisms
- Adipose Tissue and Metabolism
- Prion Diseases and Protein Misfolding
- Metabolomics and Mass Spectrometry Studies
- Bioinformatics and Genomic Networks
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Genetic Associations and Epidemiology
- Cancer-related gene regulation
- Lipid metabolism and biosynthesis
- Neurological Disease Mechanisms and Treatments
- Muscle Physiology and Disorders
- Chronic Lymphocytic Leukemia Research
- Biochemical Acid Research Studies
Broad Institute
2017-2024
Boston Children's Hospital
2021-2022
Harvard University
2022
Université de Montréal
2012-2018
Centre Hospitalier de l’Université de Montréal
2012-2016
Novartis (Switzerland)
2004
Children's Oncology Group
2004
Baylor College of Medicine
2004
Abstract Microglia, the macrophages of brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known states. Understanding state function, especially human microglia, has been elusive owing to a lack tools model and manipulate these cells. Here, we developed platform for modeling microglia states vitro. We found that exposure stem-cell-differentiated synaptosomes, myelin debris, apoptotic neurons or...
An expansion of the hexanucleotide GGGGCC repeat in first intron C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if mutation results a gain function, loss function or if, perhaps both mechanisms are pathogenesis. We generated genetic model ALS explore biological consequences null Caenorhabditis elegans orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading paralysis and specific degeneration GABAergic motor...
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, understand the unique molecular properties that may sensitize ETNs ALS, we performed RNA sequencing 79,169 single nuclei from cortices patients and controls. In both unaffected individuals, found significantly higher...
The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans zebrafish animal models expressing mutant human (A315T or G348C) (S57Δ R521H) that reflect certain aspects ALS motor neuron degeneration, axonal deficits, progressive paralysis. To explore potential our humanized...
Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches comprehensively assess diverse FFAs circulating human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report design and implementation acid library comprehensive ontologies (FALCON), an unbiased, scalable, multimodal interrogation 61 structurally FFAs. We identified a...
Intronic hexanucleotide repeat expansions in the C9orf72 gene represent most common genetic cause of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. This expansion decreases expression affected patients, indicating that loss function (LOF) acts as a pathogenic mechanism. Several models using Danio rerio (zebrafish) for depletion have been developed to explore disease mechanisms consequences LOF. However, inconsistencies exist reported phenotypes,...
Spinocerebellar ataxia type 3 is caused by the expansion of coding CAG repeat in ATXN3 gene. Interestingly, a −1 bp frameshift occurring within an expCAG would henceforth lead to translation from GCA frame, generating polyalanine stretches instead polyglutamine. Our results show that transgenic expression led frameshifting events, which have deleterious effects Drosophila and mammalian neurons. Conversely, polyglutamine-encoding expCAA was not toxic. Furthermore, mRNA does contribute per se...
Cellular perturbations underlying Alzheimer's disease are primarily studied in human postmortem samples and model organisms. Here we generated a single-nucleus atlas from rare cohort of cortical biopsies living individuals with varying degrees pathology. We next performed systematic cross-disease cross-species integrative analysis to identify set cell states that specific early AD These changes-which refer as the Early Cortical Amyloid Response-were prominent neurons, wherein identified...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing death of the motor neurons. Proteotoxicity caused by TDP-43 protein an important aspect ALS pathogenesis, with being main constituent aggregates found in patients. We have previously tested effect different sugars on proteotoxicity expression mutant Caenorhabditis elegans. Here we maple syrup, natural compound containing many active molecules including and phenols, for neuroprotective activity. Maple syrup decreased...
Abstract Microglia have emerged as key players in the pathogenesis of neurodegenerative conditions such Alzheimer’s disease (AD). In response to CNS stimuli, these cells adopt distinct transcriptional and functional subtypes known states. However, an understanding function states has been elusive, especially human microglia, due lack tools model manipulate this cell-type. Here, we provide a platform for modeling microglia vitro . Using single-cell RNA sequencing, found that exposure...
The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that reduction proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired phenotypes. are also involved regulation lifespan stress resistance, acting partially through insulin/IGF-signalling pathway. We propose maintenance lifespan, cellular resistance...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive loss of motor function. The eponymous spinal sclerosis observed at autopsy the result degeneration extratelencephalic neurons, Betz cells (ETNs, Cortico-Spinal Motor Neuron). It remains unclear why this neuronal subtype selectively affected. To understand unique molecular properties that sensitise these to ALS, we performed RNA sequencing 79,169 single nuclei from cortices patients and...
Childhood‐onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age 13. The male COS cases have slightly younger than female cases. They also present with higher rate comorbid developmental disorders. These sex differences are not explained by frequency chromosomal abnormalities, contribution other forms genetic variations remains unestablished. Using whole‐exome sequencing approach, we examined 12 trios where unaffected parents had...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder causing selective death of motor neurons in which it speculated that 10% cases have familial history. In the past 20 years, many genes causative for ALS been discovered, but link between them and their roles neurodegeneration remain unknown. The identification associated with both frontotemporal dementia (FTD), along observation patients affected by diseases, suggested they are part same spectrum. Investigating...
Abstract Background Emerging studies have identified changes in lipid processing Alzheimer’s disease patients. However, how the various brain cell types respond to these is unclear. Multiple risk genes are expressed microglia and involved sensing processing. Method In this project, we assessed unbiasedly fatty acids impact states functions. Using iPSC‐derived platform, our lab has recently developed (Dolan*, Therrien* et al. Nature Immunology 2023), characterized of 48 different on human...
Abstract Background Emerging genetic studies of late‐onset Alzheimer’s Disease (LOAD) implicate microglia, the brain’s resident macrophages. More than half risk genes associated with LOAD are expressed in yet we know little about underlying biology or how myeloid cells contribute to pathogenesis. Single‐cell transcriptomic reveal diverse microglial states patients and mouse models; however, lack tools track these understand impact environmental challenges susceptibility. Method We used human...