Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein
Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein
Abstract Parkinson′s disease (PD) pathology progresses throughout the nervous system affecting numerous neuronal structures. 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. The appearance of the pathology in dopaminergic neurons leads to neuronal cell death and motor symptoms. However, the effect on other neuronal structures is more inconsistent, leading to a higher variability in the prevalence of non-motor symptoms. Thus, the sensitivity to the pathology seems to vary among neuronal subtypes. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology and the effect of monomeric and oligomeric ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type mice. Our results showed that pathology progression did not occur in the absence of endogenous ASYN and that dopaminergic neurons were more sensitive to ASYN and rotenone when compared to all other neuronal subtypes. Remarkably, the toxic effect of ASYN was independent of the presence of endogenous ASYN and directly related to the disturbance of the mitochondrial membrane potential. Thus, we suggest that the interaction between ASYN and mitochondria plays an important role in the toxicity of trans-synaptically transported ASYN and in the progression of PD pathology. These results question the prion-disease hypothesis and propose that endocytosed ASYN impairs the host′s mitochondrial function thereby also contributing to PD-pathology progression.
Chovsepian Alexandra、Dening Yanina、Ruf Viktoria、Dirscherl Petra、Stievenard Alicia、Khairnar Amit、Herms Jochen、Dieterich Marianne、Falkai Peter、Giese Armin、Wurst Wolfgang、Schmidt Felix、Weisenhorn Daniela Vogt、Giesert Florian、Stra?l Theresa、Levin Johannes、Pan-Montojo Francisco
Department of Psychiatry, Ludwig-Maximilian University HospitalDepartment of Psychiatry, Ludwig-Maximilian University Hospital||Department of Neurology, Ludwig-Maximilian University HospitalCenter for Neuropathology und Prion Research, Ludwig-Maximilian-Universit?t M¨1nchen||Munich Cluster for Systems Neurology, SyNergyInstitute of Developmental Genetics, Helmholtz Zentrum MunichUniv. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et CancerApplied Neuroscience Research Group, CEITEC - Central European Institute of Technology, Masaryk UniversityCenter for Neuropathology und Prion Research, Ludwig-Maximilian-Universit?t M¨1nchen||Munich Cluster for Systems Neurology, SyNergy||Deutsches Zentrum f¨1r Neurodegenerative ErkrankungenDepartment of Neurology, Ludwig-Maximilian University Hospital||Munich Cluster for Systems Neurology, SyNergyDepartment of Psychiatry, Ludwig-Maximilian University HospitalCenter for Neuropathology und Prion Research, Ludwig-Maximilian-Universit?t M¨1nchen||Munich Cluster for Systems Neurology, SyNergyInstitute of Developmental Genetics, Helmholtz Zentrum Munich||Deutsches Zentrum f¨1r Neurodegenerative Erkrankungen||Technische Universit?t M¨1nchen-Weihenstephan 85764 Neuherberg/MunichDepartment of Neurology, Ludwig-Maximilian University Hospital||Center for Neuropathology und Prion Research, Ludwig-Maximilian-Universit?t M¨1nchenInstitute of Developmental Genetics, Helmholtz Zentrum MunichInstitute of Developmental Genetics, Helmholtz Zentrum MunichDepartment of Neurology, Ludwig-Maximilian University HospitalDepartment of Neurology, Ludwig-Maximilian University Hospital||Munich Cluster for Systems Neurology, SyNergy||Deutsches Zentrum f¨1r Neurodegenerative ErkrankungenDepartment of Psychiatry, Ludwig-Maximilian University Hospital||Department of Neurology, Ludwig-Maximilian University Hospital||Munich Cluster for Systems Neurology, SyNergy
神经病学、精神病学基础医学分子生物学
Chovsepian Alexandra,Dening Yanina,Ruf Viktoria,Dirscherl Petra,Stievenard Alicia,Khairnar Amit,Herms Jochen,Dieterich Marianne,Falkai Peter,Giese Armin,Wurst Wolfgang,Schmidt Felix,Weisenhorn Daniela Vogt,Giesert Florian,Stra?l Theresa,Levin Johannes,Pan-Montojo Francisco.Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.03.31.486401.点此复制
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