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

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Authors	DENING Yanina STRASSL Theresa RUF Viktoria DIRSCHERL Petra CHOVSEPIAN Alexandra STIEVENARD Alicia KHAIRNAR Amit Suresh SCHMIDT Felix GIESERT Florian HERMS Jochen LEVIN Johannes DIETERICH Marianne FALKAI Peter WEISENHORN Daniela Vogt WURST Wolfgang GIESE Armin PAN-MONTOJO Francisco
Year of publication	2022
Type	Article in Periodical
Magazine / Source	Nature Scientific Reports
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://www.nature.com/articles/s41598-022-25790-2
Doi	http://dx.doi.org/10.1038/s41598-022-25790-2
Keywords	Parkinson ' s disease; prion-like disease; endocytosed-alpha-synuclein; mitochondria
Description	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.