Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-oxic parallel beta-sheet structured species

被引：84

作者：

Gonzalez-Lizarraga, Florencia ^{[1
,2
,3
]}

Socias, Sergio B. ^{[1
,2
]}

Avila, Cesar L. ^{[1
,2
]}

Torres-Bugeau, Clarisa M. ^{[1
,2
]}

Barbosa, Leandro R. S. ^{[4
]}

Binolfi, Andres ^{[5
,6
]}

Sepulveda-Diaz, Julia E. ^{[3
]}

Del-Bel, Elaine ^{[7
,8
]}

Fernandez, Claudio O. ^{[5
,6
]}

Papy-Garcia, Dulce ^{[9
]}

Itri, Rosangela ^{[4
]}

Raisman-Vozari, Rita ^{[3
]}

Chehin, Rosana N. ^{[1
,2
]}

机构：

[1] CCT Tucuman, Inst Super Invest Biol INSIBIO, Chacabuco 461 T4000ILI, San Miguel De Tucuman, Tucuman, Argentina

[2] UNT, CONICET, Inst Quim Biol Dr Bernabe Bloj, Chacabuco 461 T4000ILI, San Miguel De Tucuman, Tucuman, Argentina

[3] UPMC Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere,ICM, INSERM,CNRS,UMR S 1127,UMR 7225,U1127, Paris, France

[4] Univ Sao Paulo, Inst Fis, Rua Matao,Travessa R 187, Sao Paulo, Brazil

[5] Univ Nacl Rosario Ocampo & Esmeralda, UNR CONICET, UNR MPIbpC, Max Planck Lab Struct Biol Chem & Mol Biophys Ros, S2002LRK, Rosario, Argentina

[6] Univ Nacl Rosario Ocampo & Esmeralda, UNR CONICET, IIDEFAR, Inst Invest Descubrimiento Farmacos Rosario, S2002LRK, Rosario, Argentina

[7] Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Morphol Physiol & Stomatol, BR-05508 Sao Paulo, Brazil

[8] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci, NAPNA, BR-05508 Sao Paulo, Brazil

[9] Univ Paris Est, Univ Paris Est Creteil, CNRS ERL 9215, CRRET,Lab Croissance Reparat & Regenerat Tissular, F-94000 Creteil, France

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

基金：

巴西圣保罗研究基金会;

关键词：

PARKINSONS-DISEASE; OXIDATIVE STRESS; COMMON MECHANISM; MINOCYCLINE; TOXICITY; NEUROPROTECTION; TRANSMISSION; AGGREGATION; MORPHOLOGY; INCLUSIONS;

D O I：

10.1038/srep41755

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：

Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes alpha-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different beta-sheet structural arrangement. These structural changes affect the alpha-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug.

引用

页数：13