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.

Applied Neuroscience Research Group CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Center for Neuropathology Und Prion Research Ludwig Maximilian Universität München Feodor Lynen Str 23 81377 Munich Germany

Department of Neurology Ludwig Maximilian University Hospital Marchioninistr 15 81377 Munich Germany

Department of Psychiatry Ludwig Maximilian University Hospital Nußbaumstr 7 80366 Munich Germany

Deutsches Zentrum Für Neurodegenerative Erkrankungen Feodor Lynen Str 17 81377 Munich Germany

Institute of Developmental Genetics Helmholtz Zentrum Munich Germany

Munich Cluster for Systems Neurology SyNergy Munich Germany

National Institute of Pharmaceutical Education and Research Ahmedabad Palaj Gandhinagar Gujarat 382355 India

Technische Universität München Weihenstephan 85764 Neuherberg Munich Germany

University Lille Inserm CHU Lille UMR S 1172 JPArc Centre de Recherche Jean Pierre AUBERT Neurosciences et Cancer 59000 Lille France

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