A5088362192- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Neurological disorders and treatments
- Advanced NMR Techniques and Applications
- Trace Elements in Health
- Nerve injury and regeneration
- Genetic Neurodegenerative Diseases
- Botulinum Toxin and Related Neurological Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Advanced MRI Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- Peroxisome Proliferator-Activated Receptors
- Neuroscience and Neuropharmacology Research
- Enzyme Structure and Function
- Heat shock proteins research
- biodegradable polymer synthesis and properties
- RNA Research and Splicing
- Protein Structure and Dynamics
- Biotin and Related Studies
- Amyotrophic Lateral Sclerosis Research
- Cholinesterase and Neurodegenerative Diseases
- RNA regulation and disease
Centre National de la Recherche Scientifique
2015-2024
Direction de la Recherche Fondamentale
2018-2024
CEA Paris-Saclay - Etablissement de Fontenay-aux-roses
2018-2024
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
2018-2024
Université Paris-Saclay
2016-2024
CEA Paris-Saclay
2022-2023
Institut des Neurosciences Paris-Saclay
2013-2020
Université Paris-Sud
2004-2018
Université de Lille
2017
Inserm
2017
α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association protein aggregates made single clinical phenotypes has been explained for prion by the existence different strains that propagate through infection pathway. Here we structurally functionally characterize two polymorphs α-synuclein. We present evidence forms indeed fulfil molecular criteria to be identified...
Objective To date, 3 rare missense mutations in the SNCA (α‐synuclein) gene and more frequent duplications or triplications of wild‐type are known to cause a broad array clinical pathological symptoms familial Parkinson disease (PD). Here, we describe French family with parkinsonian–pyramidal syndrome harboring novel heterozygous mutation. Methods Whole exome sequencing DNA from patients 3‐generation pedigree was used identify new PD‐associated mutation . Clinical features were analyzed. The...
The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest misfolded α-synuclein could behave as prion, moving from neuron and causing endogenous misfold. Here, we characterized quantified transport fibrils showed be transferred axons second-order neurons following anterograde transport.We grew primary cortical mouse microfluidic devices separate somata projections fluidically isolated...
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure fibrils (residues 1–121), composed two protofibrils that connected via densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report new polymorphic atomic structures termed polymorphs 2a and 2b, at 3.0 Å 3.4 resolution, respectively. These show radically different compared...
The origin of α‐synuclein (α‐syn)‐positive glial cytoplasmic inclusions found in oligodendrocytes multiple system atrophy (MSA) is enigmatic, given the fact that do not express α‐syn mRNA. Recently, neuron‐to‐neuron transfer was suggested to contribute pathogenesis Parkinson's disease. In this study, we explored whether a similar might occur from neurons oligodendrocytes, which conceivably could explain how are formed. We studied vitro and vivo examined their ability take up different...
α-Synuclein (α-syn) is a protein prevalent in neural tissue and known to undergo axonal transport. Intracellular α-syn aggregates are hallmark of Parkinson's disease (PD). Braak collaborators have suggested that people who destined eventually develop PD, aggregate pathology progresses following stereotypic pattern, starting the olfactory bulb (OB) gut. postulated spread interconnected brain regions over several years. Thus, propagation via pathways can potentially explain how PD. We now...
Microglia jointly degrade fibrillar
A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer are found various types, including neurons. We show the microtubule-associated protein Tau, key player Alzheimer's disease, is bona fide constituent TNTs. This important because Tau...
Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout nervous but diverge from one another regard to their clinical pathological phenotype. The recent generation pure fibrillar αSYN polymorphs noticeable differences in structural phenotypic traits has led hypothesis that different strains may be part responsible for heterogeneous nature synucleinopathies....
Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested may be secreted and play role neural network signalling. However, once deregulated, also participate the spreading of pathology hierarchical pathways neurodegeneration. The mechanisms underlying neuron-to-neuron transfer are still unknown; given extra-cellular vesicles cell-to-cell communication, we wondered whether these could carry Tau. We found,...
Progressive aggregation of the protein alpha-synuclein (α-syn) and loss dopaminergic neurons in substantia nigra pars compacta (SNpc) are key histopathological hallmarks Parkinson's disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits brain, contributing to progressive nature disease. Thus, it is therapeutically pertinent identify modifiers transmission as potential targets slow down progression. A growing number genetic mutations risk factors...
Accruing evidence suggests that prion-like behavior of fibrillar forms α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread lesions characterize Parkinson disease, Alzheimer disease Huntington respectively. It is unknown whether these distinct protein assemblies transported within between neurons by similar or mechanisms. also unclear if neuronal death injury required neuron-to-neuron transfer. To address questions, we used mouse primary cortical grown in...
Objective Excessive inflammation in the central nervous system (CNS) and periphery can result neurodegeneration parkinsonism. Recent evidence suggests that immune responses Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction unspecific triggers. Although α‐synuclein pathology is hallmark of disease, it has not been investigated whether pathologic a specific trigger for excessive disease. Methods We response primary human monocytes microglial cell line...
The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles fibrils vitro We found this function mediated by the core HSC70, assisted specific cochaperones, particular class B J-domain proteins a heat shock 110 (Hsp110)-type nucleotide exchange factor (NEF). Hsp70 disaggregation machinery processed recombinant...
We structurally compare, using solid-state NMR, two different polymorphs of α-synuclein which, as established recently, display contrasting biochemical properties, toxicity, and tropism for cells. show that both forms, which can each be produced a pure polymorph, are greatly in secondary structure. While β-sheets the dominating structure elements polymorphs, they markedly divergent terms number elements, well their distribution. demonstrate all identified feature an in-register parallel...
Reappraisal of neuropathological studies suggests that pathological hallmarks Alzheimer's disease and Parkinson's (PD) spread progressively along predictable neuronal pathways in the human brain through unknown mechanisms. Although there is much evidence supporting prion-like propagation amplification α-synuclein (α-Syn) vitro rodent models, whether this scenario occurs remains to be substantiated. Here we reconstructed microfluidic devices corticocortical networks using induced pluripotent...