High Stability and Cooperative Unfolding of α-Synuclein Oligomers

被引:63
作者
Paslawski, Wojciech [1 ,2 ]
Andreasen, Maria [1 ,2 ]
Nielsen, Soren Bang [1 ,2 ]
Lorenzen, Nikolai [1 ,2 ]
Thomsen, Karen [1 ]
Kaspersen, Jorn Dovling [1 ,3 ]
Pedersen, Jan Skov [1 ,3 ]
Otzen, Daniel E. [1 ,2 ]
机构
[1] Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus C, Denmark
[2] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark
[3] Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark
关键词
SMALL-MOLECULE INHIBITORS; AMYLOID-BETA; PARKINSONS-DISEASE; VESICLE PERMEABILIZATION; ALZHEIMERS-DISEASE; DISORDERED MONOMER; AGGREGATION; MUTATION; FIBRILLIZATION; FIBRILLATION;
D O I
10.1021/bi5007833
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Many neurodegenerative diseases are linked with formation of amyloid aggregates. It is increasingly accepted that not the fibrils but rather oligomeric species are responsible for degeneration of neuronal cells. Strong evidence suggests that in Parkinson's disease (PD), cytotoxic alpha-synuclein (alpha SN) oligomers are key to pathogenicity. Nevertheless, insight into the oligomers' molecular properties remains scarce. Here we show that alpha SN oligomers, despite a large amount of disordered structure, are remarkably stable against extreme pH, temperature, and even molar amounts of chemical denaturants, though they undergo cooperative unfolding at higher denaturant concentrations. Mutants found in familial PD lead to slightly larger oligomers whose stabilities are very similar to that of wild-type alpha SN. Isolated oligomers do not revert to monomers but predominantly form larger aggregates consisting of stacked oligomers, suggesting that they are off-pathway relative to the process of fibril formation. We also demonstrate that 4-(dicyanovinyl)julolidine (DCVJ) can be used as a specific probe for detection of alpha SN oligomers. The high stability of the alpha SN oligomer indicates that therapeutic strategies should aim to prevent the formation of or passivate rather than dissociate this cytotoxic species.
引用
收藏
页码:6252 / 6263
页数:12
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[41]   Targeting Oligomers in Neurodegenerative Disorders: Lessons from α-Synuclein, Tau, and Amyloid-β Peptide [J].
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[47]   Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy [J].
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Murillo, Mariana Carretero ;
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