The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies

Autor: Chris Van den Haute, Géraldine Gelders, Anke Van der Perren, Steve M. Gentleman, Alexis Fenyi, Veerle Baekelandt, Wouter Peelaerts, Filipa De Brito, Ronald Melki, Luc Bousset
Přispěvatelé: Laboratory for Neurobiology and Gene Therapy, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Viral Vector Core, Imperial College London, ANR-17-JPCD-0002-02, ANR‐11‐IDEX‐0003‐02, ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-15-JPWG-0012,SYNACTION,Unravelling the pathophysiological role of alpha-synuclein aggregation, transmission and neuroinflammation in neurodegeneration(2015), European Project: 289964,EC:FP7:PEOPLE,FP7-PEOPLE-2011-ITN,TRANSPATH(2011), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Parkinson's disease
Synucleinopathies
alpha-synuclein
[SDV]Life Sciences [q-bio]
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
ASSEMBLIES
Strains
chemistry.chemical_compound
0302 clinical medicine
OLIGOMERS
RAT MODEL
Aged
80 and over
0303 health sciences
Neurodegeneration
NEURODEGENERATION
Brain
Parkinson Disease
Human brain
Middle Aged
Phenotype
3. Good health
medicine.anatomical_structure
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Life Sciences & Biomedicine
Lewy Body Disease
TRANSMISSION
Clinical Neurology
Biology
DIAGNOSIS
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Atrophy
α-synuclein
mental disorders
medicine
Humans
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Aged
030304 developmental biology
Alpha-synuclein
Original Paper
Neurology & Neurosurgery
Science & Technology
Dementia with Lewy bodies
Neurosciences
1103 Clinical Sciences
Multiple System Atrophy
AGGREGATION
medicine.disease
INCLUSIONS
nervous system diseases
PATHOLOGY
chemistry
nervous system
Neurodegenerative disorders
Dementia
Neurology (clinical)
Neurosciences & Neurology
OVEREXPRESSION
1109 Neurosciences
Neuroscience
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica
Acta Neuropathologica, 2020, ⟨10.1007/s00401-020-02157-3⟩
Acta Neuropathologica, Springer Verlag, 2020, ⟨10.1007/s00401-020-02157-3⟩
ISSN: 0001-6322
1432-0533
DOI: 10.1007/s00401-020-02157-3⟩
Popis: 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 the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains. ispartof: Acta Neuropathologica vol:139 issue:6 pages:977-1000 ispartof: location:Germany status: published
Databáze: OpenAIRE
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