PT  - JOURNAL ARTICLE
AU  - Yanina Dening
AU  - Theresa Straßl
AU  - Viktoria Ruf
AU  - Petra Dirscherl
AU  - Alexandra Chovsepian
AU  - Alicia Stievenard
AU  - Amit Khairnar
AU  - Felix Schmidt
AU  - Florian Giesert
AU  - Jochen Herms
AU  - Johannes Levin
AU  - Marianne Dieterich
AU  - Peter Falkai
AU  - Daniela Vogt Weisenhorn
AU  - Wolfgang Wurst
AU  - Armin Giese
AU  - Francisco Pan-Montojo
TI  - Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein
AID  - 10.1101/2022.03.31.486401
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.31.486401
4099  - http://biorxiv.org/content/early/2022/04/04/2022.03.31.486401.short
4100  - http://biorxiv.org/content/early/2022/04/04/2022.03.31.486401.full
AB  - 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.Competing Interest StatementJohannes Levin reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG, outside the submitted work. Francisco Pan-Montojo reports consulting fees as external CSO from NEUREVO GmbH, also outside the submitted work. All other authors declare no conflict of interest.ASYNalpha-synucleinPDParkinson’s DiseaseBSBlocking solutionCNSCentral nervous systemDIVDay in vitroDMVMotor nucleus of the vagusDSDonkey serumECARExtracellular acidification rateENSEnteric nervous systemFACSFluorescence Activated Cell SortingFCCPCarbonyl cyanide-4 (trifluoromethoxy) phenylhydrazoneGFPGreen-fluorescent proteinIMLIntermediolateral nucleus of the spinal cordKOKnock-outLBLewy bodiesLNLewy neuritesMFIMean fluorescence intensityNeuNNeuronal nucleiNGFNerve growth factorOBOlfactory bulbOCRMitochondrial Oxygen consumption ratePBSPhosphate buffered salinePFAParaformaldehydePGP9.5Protein gene product 9.5RBDREM sleep behaviour disorderREMRapid eye movementRORotenoneRTRoom temperatureSNcSubstantia nigra pars compactaTHTyrosine hydroxylaseTMRETetramethylrhodamine, ethyl esterWTWild-type