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

Dening, Yanina; Straßl, Theresa; Ruf, Viktoria; Dirscherl, Petra; Chovsepian, Alexandra; Stievenard, Alicia; Khairnar, Amit; Schmidt, Felix; Giesert, Florian; Herms, Jochen; Levin, Johannes; Dieterich, Marianne; Falkai, Peter; Weisenhorn, Daniela Vogt; Wurst, Wolfgang; Giese, Armin und Pan-Montojo, Francisco (19. December 2022): Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein. In: Scientific Reports, Vol. 12, No. 1

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.

• Item Type: Journal article
• Faculties: Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Psychiatry and Psychotherapy
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2045-2322
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892