Journal Article

DZNE-2023-00042

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein.

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

2022
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-022-25790-2

Abstract: 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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; alpha-Synuclein (MeSH) ; Rotenone: therapeutic use (MeSH) ; Paraquat (MeSH) ; Parkinson Disease: pathology (MeSH) ; Dopaminergic Neurons: pathology (MeSH) ; alpha-Synuclein ; Rotenone ; Paraquat

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)
2. Translational Brain Research (AG Herms)
3. Clinical Dementia Research München (Clinical Dementia Research München)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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