Identical Seeding Characteristics and Cryo‐EM Filament Structures in FTLD‐Synuclein and Typical Multiple System Atrophy
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Le résumé fourni par la source
AIMS: The aim of this study is to identify the prevalence of frontotemporal dementia (FTD)/corticobasal syndrome (CBS) in a large cohort of pathologically confirmed cases of multiple system atrophy (MSA) and to determine the α-synuclein seeding characteristics and electron cryo-microscopy (cryo-EM) filament structure in frontotemporal lobar degeneration with MSA-type α-synuclein pathology (FTLD-synuclein). METHODS: The archives of the Queen Square Brain Bank (1989-2023) were searched for histologically confirmed MSA cases, and those with a clinical diagnosis of FTD/CBS were reviewed for pathological features of FTLD-synuclein. Phosphotungstic acid (PTA)-precipitated brain homogenates from FTLD-synuclein, dementia with Lewy bodies (DLB) and G51D SNCA synucleinopathy cases were used to seed aggregation in α-syn140*A53T-YFP HEK293T cells. The structure of α-synuclein filaments from an FTLD-synuclein case was determined by cryo-EM. RESULTS: We identified 283 cases of MSA. Four cases had a clinical diagnosis of CBS, one of which met pathological criteria for FTLD-synuclein. Genetic studies in this case were negative for SNCA variants, and PTA-precipitated brain homogenates seeded abundant cytoplasmic α-synuclein inclusions that were morphologically indistinguishable from those of typical MSA but distinct from those of G51D SNCA and DLB. MSA Type II α-synuclein filaments were identified by cryo-EM. CONCLUSIONS: FTD/CBS is rarely associated with MSA pathology. The cell seeding characteristics and cryo-EM findings support the classification of FTLD-synuclein as a subtype of MSA, differentiating it from genetic synucleinopathies, such as those with SNCA variants G51D and A53E, which have neuropathological features overlapping with MSA and Lewy body diseases. These cases expand the clinicopathological spectrum of MSA and FTLD and have implications for our understanding of selective neuronal vulnerability in MSA and the interpretation of α-synuclein biomarker studies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Identical Seeding Characteristics and Cryo‐EM Filament Structures in FTLD‐Synuclein and Typical Multiple System Atrophy
- Date Crossref
- 26/03/2025
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Hospital for Neurology and Neurosurgery Division of Neuropathology pays non établi dans la noticeÉtablissement de santé
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UCL Queen Square Institute of Neurology Queen Square Brain Bank for Neurological Disorders pays non établi dans la noticeUniversité ou école supérieure
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University College London National Hospital for Neurology and Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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Van Andel Institute Department of Structural Biology pays non établi dans la noticeOrganisation à but non lucratif
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MRC Laboratory of Molecular Biology pays non établi dans la noticeStructure de recherche
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Medical Research Council pays non établi dans la noticeOrganisme public
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Colorado State University Department of Microbiology pays non établi dans la noticeUniversité ou école supérieure
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University College London Hospitals NHS Foundation Trust pays non établi dans la noticeÉtablissement de santé
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Department of Clinical and Movement Neurosciences pays non établi dans la noticeÉtablissement de santé
Division of Neuropathology — National Hospital for Neurology and Neurosurgery, Queen Square Brain Bank for Neurological Disorders — UCL Queen Square Institute of Neurology et National Hospital for Neurology and Neurosurgery — University College London, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.