Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies
Rattachement africain : fr, ch, gb, se, be. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Alpha-synuclein (aSyn) post-translational modifications (PTMs), particularly phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LBs), Lewy neurites, and other types of aSyn pathological aggregates in the brain of patients with Parkinson’s disease (PD) and other synucleinopathies. However, our knowledge about the precise role of PTMs in regulating the different stages of pathology formation, neurodegeneration, and aSyn pathology spreading remains incomplete. In this work, we applied a systematic approach to address this knowledge gap with an emphasis on mapping and elucidating the role of post-fibrillization C-terminal aSyn truncations in regulating the uptake, processing, seeding activity, and formation of LB-like inclusions and maturations in a well-established neuronal seeding model that recapitulates all the stages leading to LB formation and neurodegeneration. Our work shows that C-terminal cleavage of aSyn fibrils at multiple sites is a conserved process that occurs rapidly after and during the formation of intracellular LB-like aSyn inclusions in all neuronal seeding models. Interestingly, blocking the cleavage of internalized fibrils does not influence their seeding activity, whereas inhibiting the enzymes that regulate the cleavage of newly formed fibrils (e.g., calpains 1 and 2) significantly alters the formation of LB-like inclusions. We also show that C-terminal truncations, in combination with other PTMs, play a crucial role in regulating the interactome and remodeling of newly formed aSyn fibrils, including their shortening, lateral association, and packing during LB formation and maturation. Altogether, our results demonstrate that post-fibrillization C-terminal truncations have a differential role at different stages of aSyn aggregation and pathology formation. These insights, combined with the abundance of truncated aSyn species in LBs, have significant implications in understanding aSyn pathological diversity and developing therapeutic strategies targeting the C-terminus of aSyn or its proteolytic processing.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies
- Date Crossref
- 30/11/2024
- Éditeur
- openRxiv
- Type
- posted-content
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
-
Laboratoire d'Informatique Fondamentale de Lille pays non établi dans la noticeStructure de recherche
-
École Polytechnique Fédérale de Lausanne Laboratory of Molecular and Chemical Biology of Neurodegeneration pays non établi dans la noticeUniversité ou école supérieure
-
University of Oxford pays non établi dans la noticeUniversité ou école supérieure
-
Lund University Department of Experimental Medical Science pays non établi dans la noticeUniversité ou école supérieure
-
UCB Pharma (Belgium) pays non établi dans la noticeEntreprise
-
EPFL pays non établi dans la noticeInstitution
-
UCL Institute of Neurology pays non établi dans la noticeStructure de recherche
-
Proteomic Core Facility and Technology Platform pays non établi dans la noticeInstitution
-
BioEM Core Facility and Technology Platform pays non établi dans la noticeInstitution
-
UCB Biopharma SPRL pays non établi dans la noticeInstitution
Laboratoire d'Informatique Fondamentale de Lille, Laboratory of Molecular and Chemical Biology of Neurodegeneration — École Polytechnique Fédérale de Lausanne et University of Oxford, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.