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Dening, Y.* ; Straßl, T.* ; Ruf, V.* ; Dirscherl, P. ; Chovsepian, A.* ; Stievenard, A.* ; Khairnar, A.* ; Schmidt, F.* ; Giesert, F. ; Herms, J.* ; Levin, J.* ; Dieterich, M.* ; Falkai, P.* ; Weisenhorn, D.M. ; Wurst, W. ; Giese, A.* ; Pan-Montojo, F.*

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein.

Sci. Rep. 12:21951 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Journal Scientific Reports
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 21951 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Grants Projekt DEAL