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Pre‐fibrillar α‐synuclein variants with impaired β‐structure increase neurotoxicity in Parkinson's disease models
Author(s) -
Karpinar Damla Pinar,
Balija Madhu Babu Gajula,
Kügler Sebastian,
Opazo Felipe,
RezaeiGhaleh Nasrollah,
Wender Nora,
Kim HaiYoung,
Taschenberger Grit,
Falkenburger Björn H,
Heise Henrike,
Kumar Ashutosh,
Riedel Dietmar,
Fichtner Lars,
Voigt Aaron,
Braus Gerhard H,
Giller Karin,
Becker Stefan,
Herzig Alf,
Baldus Marc,
Jäckle Herbert,
Eimer Stefan,
Schulz Jörg B,
Griesinger Christian,
Zweckstetter Markus
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.257
Subject(s) - biology , neurotoxicity , alpha synuclein , caenorhabditis elegans , in vivo , drosophila melanogaster , mutant , parkinson's disease , microbiology and biotechnology , biophysics , biochemistry , toxicity , genetics , disease , chemistry , gene , medicine , organic chemistry , pathology
The relation of α‐synuclein (αS) 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 αS species have in neurotoxicity in vivo , we generated αS variants by a structure‐based rational design. Biophysical analysis revealed that the αS 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 αS 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 αS aggregates with impaired β‐structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric αS species and their in vivo function.