Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models.
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.
Karpinar
Damla Pinar
DP
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, Göttingen, Germany.
Balija
Madhu Babu Gajula
MB
Kügler
Sebastian
S
Opazo
Felipe
F
Rezaei-Ghaleh
Nasrollah
N
Wender
Nora
N
Kim
Hai-Young
HY
Taschenberger
Grit
G
Falkenburger
Björn H
BH
Heise
Henrike
H
Kumar
Ashutosh
A
Riedel
Dietmar
D
Fichtner
Lars
L
Voigt
Aaron
A
Braus
Gerhard H
GH
Giller
Karin
K
Becker
Stefan
S
Herzig
Alf
A
Baldus
Marc
M
Jäckle
Herbert
H
Eimer
Stefan
S
Schulz
Jörg B
JB
Griesinger
Christian
C
Zweckstetter
Markus
M
D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D051844:alpha-Synuclein