Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 12 2022
19 12 2022
Historique:
received:
15
06
2022
accepted:
05
12
2022
entrez:
19
12
2022
pubmed:
20
12
2022
medline:
22
12
2022
Statut:
epublish
Résumé
Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target.
Identifiants
pubmed: 36535974
doi: 10.1038/s41598-022-25790-2
pii: 10.1038/s41598-022-25790-2
pmc: PMC9763379
doi:
Substances chimiques
alpha-Synuclein
0
Rotenone
03L9OT429T
Paraquat
PLG39H7695
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
21951Informations de copyright
© 2022. The Author(s).
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