In vivo demonstration that α-synuclein oligomers are toxic

被引：1152

作者：

Winner, Beate ^{[1
,2
]}

Jappelli, Roberto ^{[1
]}

Maji, Samir K. ^{[3
]}

Desplats, Paula A. ^{[4
,5
]}

Boyer, Leah ^{[1
,6
]}

Aigner, Stefan ^{[1
]}

Hetzer, Claudia ^{[1
]}

Loher, Thomas ^{[1
]}

Vilar, Marcal ^{[1
]}

Campioni, Silvia ^{[3
]}

Tzitzilonis, Christos ^{[1
]}

Soragni, Alice ^{[3
]}

Jessberger, Sebastian ^{[1
,7
]}

Mira, Helena ^{[1
]}

Consiglio, Antonella ^{[1
]}

Pham, Emiley ^{[4
,5
]}

Masliah, Eliezer ^{[4
,5
]}

Gage, Fred H. ^{[1
]}

Riek, Roland ^{[1
,3
]}

机构：

[1] Salk Inst Biol Studies, La Jolla, CA 92037 USA

[2] Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Interdisciplinary Ctr Clin Res, Jr Res Grp 3, D-91054 Erlangen, Germany

[3] ETH, Phys Chem Lab, CH-8093 Zurich, Switzerland

[4] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Sch Med, Biomed Sci Grad Program, La Jolla, CA 92093 USA

[7] ETH, Inst Cell Biol, CH-8093 Zurich, Switzerland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 10期

基金：

美国国家卫生研究院;

关键词：

LEWY BODY DEMENTIA; SOLID-STATE NMR; PARKINSONS-DISEASE; SECONDARY STRUCTURE; FIBRILS; BETA; MUTATIONS; MODEL; PATHOGENESIS; PORES;

D O I：

10.1073/pnas.1100976108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of alpha-synuclein (alpha-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed alpha-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the alpha-syn variants that form oligomers (i.e., E57K and E35K), whereas the alpha-syn variants that form fibrils very quickly are less toxic. We show that a-syn oligomers are toxic in vivo and that alpha-syn oligomers might interact with and potentially disrupt membranes.

引用

页码：4194 / 4199

页数：6

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