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
相关论文
共 50 条
[31]   Levels of α- and β-synuclein regulate cellular susceptibility to toxicity from α-synuclein oligomers [J].
Angelova, Dafina M. ;
Jones, Hannah B. L. ;
Brown, David R. .
FASEB JOURNAL, 2018, 32 (02) :995-1006
[32]   Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology [J].
Danzer, Karin M. ;
Krebs, Simon K. ;
Wolff, Michael ;
Birk, Gerald ;
Hengerer, Bastian .
JOURNAL OF NEUROCHEMISTRY, 2009, 111 (01) :192-203
[33]   Optical Structural Analysis of Individual α-Synuclein Oligomers [J].
Varela, Juan A. ;
Rodrigues, Margarida ;
De, Suman ;
Flagmeier, Patrick ;
Gandhi, Sonia ;
Dobson, Christopher M. ;
Klenerman, David ;
Lee, Steven F. .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2018, 57 (18) :4886-4890
[34]   Characterization of the Non-Fibrillar α-Synuclein Oligomers [J].
Hong, Dong-Pyo ;
Han, Shubo ;
Fink, Anthony L. ;
Uversky, Vladimir N. .
PROTEIN AND PEPTIDE LETTERS, 2011, 18 (03) :230-240
[35]   Structural and functional properties of prefibrillar α-synuclein oligomers [J].
Pieri, Laura ;
Madiona, Karine ;
Melki, Ronald .
SCIENTIFIC REPORTS, 2016, 6
[36]   Cytotoxic Oligomers and Fibrils Trapped in a Gel-like State of α-Synuclein Assemblies [J].
Kumar, Rakesh ;
Das, Subhadeep ;
Mohite, Ganesh M. ;
Rout, Saroj K. ;
Halder, Saayak ;
Jha, Narendra Nath ;
Ray, Soumik ;
Mehra, Surabhi ;
Agarwal, Vipin ;
Maji, Samir K. .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2018, 57 (19) :5262-5266
[37]   Kinetic measurements give new insights into lipid membrane permeabilization by α-synuclein oligomers [J].
Stockl, Martin ;
Claessens, Mireille M. A. E. ;
Subramaniam, Vinod .
MOLECULAR BIOSYSTEMS, 2012, 8 (01) :338-345
[38]   α-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities [J].
Alam, Parvez ;
Bousset, Luc ;
Melki, Ronald ;
Otzen, Daniel E. .
JOURNAL OF NEUROCHEMISTRY, 2019, 150 (05) :522-534
[39]   Molecular Rotors Detect the Formation and Conversion of α-Synuclein Oligomers [J].
Allerton, Sian C. ;
Kuimova, Marina K. ;
Aprile, Francesco A. .
ACS APPLIED MATERIALS & INTERFACES, 2025, 17 (07) :10499-10508
[40]   Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration [J].
Mor, Danielle E. ;
Tsika, Elpida ;
Mazzulli, Joseph R. ;
Gould, Neal S. ;
Kim, Hanna ;
Daniels, Malcolm J. ;
Doshi, Shachee ;
Gupta, Preetika ;
Grossman, Jennifer L. ;
Tan, Victor X. ;
Kalb, Robert G. ;
Caldwell, Kim A. ;
Caldwell, Guy A. ;
Wolfe, John H. ;
Ischiropoulos, Harry .
NATURE NEUROSCIENCE, 2017, 20 (11) :1560-+