163870 20240619101458.0 10.1038/emboj.2009.257 doi pmid:19745811 pmid pmc:PMC2771093 pmc 0261-4189 ISSN 1460-2075 ISSN DZNE-2022-00557 English 570 Karpinar, Damla Pinar 0 Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. Hoboken, NJ [u.a.] 2009 Wiley article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1718784860_8362 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote The relation of alpha-synuclein (alphaS) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated alphaS species have in neurotoxicity in vivo, we generated alphaS variants by a structure-based rational design. Biophysical analysis revealed that the alphaS mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar alphaS mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between alphaS aggregates with impaired beta-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric alphaS species and their in vivo function. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de alpha-Synuclein NLM Chemicals Animals MeSH Animals, Genetically Modified MeSH Brain: metabolism MeSH Brain: pathology MeSH Caenorhabditis elegans: metabolism MeSH Cell Line MeSH Disease Models, Animal MeSH Drosophila: metabolism MeSH Humans MeSH Magnetic Resonance Spectroscopy MeSH Neurons: metabolism MeSH Neurons: pathology MeSH Parkinson Disease: metabolism MeSH Parkinson Disease: pathology MeSH Protein Multimerization MeSH Protein Structure, Secondary MeSH Rats MeSH alpha-Synuclein: chemistry MeSH alpha-Synuclein: genetics MeSH alpha-Synuclein: metabolism MeSH Balija, Madhu Babu Gajula 1 Kügler, Sebastian 2 Opazo, Felipe 3 Rezaei-Ghaleh, Nasrollah P:(DE-2719)9000418 4 dzne Wender, Nora 5 Kim, Hai-Young 6 Taschenberger, Grit 7 Falkenburger, Björn H P:(DE-2719)2814178 8 Heise, Henrike 9 Kumar, Ashutosh 10 Riedel, Dietmar 11 Fichtner, Lars 12 Voigt, Aaron 13 Braus, Gerhard H 14 Giller, Karin 15 Becker, Stefan 16 Herzig, Alf 17 Baldus, Marc 18 Jäckle, Herbert 19 Eimer, Stefan 20 Schulz, Jörg B 21 Griesinger, Christian 22 Zweckstetter, Markus P:(DE-2719)2810591 23 dzne 10.1038/emboj.2009.257 Vol. 28, no. 20, p. 3256 - 3268 PERI:(DE-600)1467419-1 20 3256 - 3268 The EMBO journal 28 2009 0261-4189 https://www.embopress.org/doi/full/10.1038/emboj.2009.257 http://pub.dzne.de/record/163870/files/DZNE-2022-00557_Restricted.pdf http://pub.dzne.de/record/163870/files/DZNE-2022-00557_Restricted.pdf?subformat=pdfa pdfa External Institute I:(DE-HGF)0 Extern 4 P:(DE-2719)9000418 External Institute I:(DE-HGF)0 Extern 8 P:(DE-2719)2814178 External Institute I:(DE-HGF)0 Extern 23 P:(DE-2719)2810591 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-353 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Clinical and Health Care Research 0 DEAL Wiley StatID:(DE-HGF)3001 StatID 2021-01-30 ger JCR StatID:(DE-HGF)0100 StatID EMBO J : 2019 2021-01-30 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2021-01-30 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2021-01-30 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2021-01-30 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2021-01-30 Peer Review StatID:(DE-HGF)0030 StatID ASC 2021-01-30 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2021-01-30 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2021-01-30 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-30 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2021-01-30 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-30 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-30 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2021-01-30 IF >= 5 StatID:(DE-HGF)9905 StatID EMBO J : 2019 2021-01-30 yes journal I:(DE-2719)1710012 I:(DE-2719)1040260 EXTERN4VITA