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@ARTICLE{Karpinar:163870,
author = {Karpinar, Damla Pinar and Balija, Madhu Babu Gajula and
Kügler, Sebastian and Opazo, Felipe and Rezaei-Ghaleh,
Nasrollah and Wender, Nora and Kim, Hai-Young and
Taschenberger, Grit and Falkenburger, Björn H and Heise,
Henrike and Kumar, Ashutosh and Riedel, Dietmar and
Fichtner, Lars and Voigt, Aaron and Braus, Gerhard H and
Giller, Karin and Becker, Stefan and Herzig, Alf and Baldus,
Marc and Jäckle, Herbert and Eimer, Stefan and Schulz,
Jörg B and Griesinger, Christian and Zweckstetter, Markus},
title = {{P}re-fibrillar alpha-synuclein variants with impaired
beta-structure increase neurotoxicity in {P}arkinson's
disease models.},
journal = {The EMBO journal},
volume = {28},
number = {20},
issn = {0261-4189},
address = {Hoboken, NJ [u.a.]},
publisher = {Wiley},
reportid = {DZNE-2022-00557},
pages = {3256 - 3268},
year = {2009},
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.},
keywords = {Animals / Animals, Genetically Modified / Brain: metabolism
/ Brain: pathology / Caenorhabditis elegans: metabolism /
Cell Line / Disease Models, Animal / Drosophila: metabolism
/ Humans / Magnetic Resonance Spectroscopy / Neurons:
metabolism / Neurons: pathology / Parkinson Disease:
metabolism / Parkinson Disease: pathology / Protein
Multimerization / Protein Structure, Secondary / Rats /
alpha-Synuclein: chemistry / alpha-Synuclein: genetics /
alpha-Synuclein: metabolism / alpha-Synuclein (NLM
Chemicals)},
ddc = {570},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:19745811},
pmc = {pmc:PMC2771093},
doi = {10.1038/emboj.2009.257},
url = {https://pub.dzne.de/record/163870},
}