Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models

被引：380

作者：

Karpinar, Damla Pinar ^{[1
,2
,3
]}

Balija, Madhu Babu Gajula ^{[1
,2
,3
]}

Kuegler, Sebastian ^{[2
,4
]}

Opazo, Felipe ^{[2
,5
]}

Rezaei-Ghaleh, Nasrollah ^{[1
]}

Wender, Nora ^{[6
]}

Kim, Hai-Young ^{[1
]}

Taschenberger, Grit ^{[4
]}

Falkenburger, Bjoern H. ^{[2
,5
]}

Heise, Henrike ^{[1
]}

Kumar, Ashutosh ^{[1
]}

Riedel, Dietmar ^{[7
]}

Fichtner, Lars ^{[2
,8
]}

Voigt, Aaron ^{[2
,5
]}

Braus, Gerhard H. ^{[2
,8
]}

Giller, Karin ^{[1
]}

Becker, Stefan ^{[1
]}

Herzig, Alf ^{[9
]}

Baldus, Marc ^{[1
]}

Jaeckle, Herbert ^{[9
]}

Eimer, Stefan ^{[2
,6
]}

Schulz, Joerg B. ^{[2
,5
]}

Griesinger, Christian ^{[1
,2
]}

Zweckstetter, Markus ^{[1
,2
]}

机构：

[1] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany

[2] DFG Res Ctr Mol Physiol Brain, Gottingen, Germany

[3] Int Max Planck Res Sch Mol Biol, Gottingen, Germany

[4] Univ Gottingen, Dept Neurol, Sch Med, D-37077 Gottingen, Germany

[5] Univ Gottingen, Ctr Neurol Med, Dept Neurodegenerat & Restorat Res, D-37073 Gottingen, Germany

[6] European Neurosci Inst, Mol Neurogenet Grp, D-37077 Gottingen, Germany

[7] Max Planck Inst Biophys Chem, Dept Electron Microscopy, D-37077 Gottingen, Germany

[8] Univ Gottingen, Dept Microbiol & Mol Genet, Inst Microbiol & Genet, D-37073 Gottingen, Germany

[9] Max Planck Inst Biophys Chem, Dept Mol Dev Biol, D-37077 Gottingen, Germany

来源：

EMBO JOURNAL | 2009年 / 28卷 / 20期

关键词：

neurodegeneration; oligomer; Parkinson's disease; structure; alpha-synuclein; DROSOPHILA MODEL; E46K MUTATION; WILD-TYPE; PROTEIN; STATE; FIBRILLIZATION; POLYMORPHISM; SEQUENCE; SYSTEM; DEATH;

D O I：

10.1038/emboj.2009.257

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The relation of alpha-synuclein (alpha S) 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 alpha S species have in neurotoxicity in vivo, we generated alpha S variants by a structure-based rational design. Biophysical analysis revealed that the alpha S 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 alpha S 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 alpha S aggregates with impaired beta-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric aS species and their in vivo function. The EMBO Journal (2009) 28, 3256-3268. doi:10.1038/emboj.2009.257; Published online 10 September 2009

引用

页码：3256 / 3268

页数：13

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