Journal Article

DZNE-2022-00557

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models.

Karpinar, D. P. ; Balija, M. B. G. ; Kügler, S. ; Opazo, F. ; Rezaei-Ghaleh, N.Extern* ; Wender, N. ; Kim, H.-Y. ; Taschenberger, G. ; Falkenburger, B. H.Extern* ; Heise, H. ; Kumar, A. ; Riedel, D. ; Fichtner, L. ; Voigt, A. ; Braus, G. H. ; Giller, K. ; Becker, S. ; Herzig, A. ; Baldus, M. ; Jäckle, H. ; Eimer, S. ; Schulz, J. B. ; Griesinger, C. ; Zweckstetter, M.Extern*

2009
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.1038/emboj.2009.257

Abstract: 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.

Keyword(s): 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) ; alpha-Synuclein

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Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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