TY  - JOUR
AU  - Karpinar, Damla Pinar
AU  - Balija, Madhu Babu Gajula
AU  - Kügler, Sebastian
AU  - Opazo, Felipe
AU  - Rezaei-Ghaleh, Nasrollah
AU  - Wender, Nora
AU  - Kim, Hai-Young
AU  - Taschenberger, Grit
AU  - Falkenburger, Björn H
AU  - Heise, Henrike
AU  - Kumar, Ashutosh
AU  - Riedel, Dietmar
AU  - Fichtner, Lars
AU  - Voigt, Aaron
AU  - Braus, Gerhard H
AU  - Giller, Karin
AU  - Becker, Stefan
AU  - Herzig, Alf
AU  - Baldus, Marc
AU  - Jäckle, Herbert
AU  - Eimer, Stefan
AU  - Schulz, Jörg B
AU  - Griesinger, Christian
AU  - Zweckstetter, Markus
TI  - Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models.
JO  - The EMBO journal
VL  - 28
IS  - 20
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00557
SP  - 3256 - 3268
PY  - 2009
AB  - 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.
KW  - Animals
KW  - Animals, Genetically Modified
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Caenorhabditis elegans: metabolism
KW  - Cell Line
KW  - Disease Models, Animal
KW  - Drosophila: metabolism
KW  - Humans
KW  - Magnetic Resonance Spectroscopy
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Protein Multimerization
KW  - Protein Structure, Secondary
KW  - Rats
KW  - alpha-Synuclein: chemistry
KW  - alpha-Synuclein: genetics
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:19745811
C2  - pmc:PMC2771093
DO  - DOI:10.1038/emboj.2009.257
UR  - https://pub.dzne.de/record/163870
ER  -