Rifampicin inhibits α-synuclein fibrillation and disaggregates fibrils

被引：192

作者：

Li, J ^{[1
]}

Zhu, M ^{[1
]}

Rajamani, S ^{[1
]}

Uversky, VN ^{[1
]}

Fink, AL ^{[1
]}

机构：

[1] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA

来源：

CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 11期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1016/j.chembiol.2004.08.025

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：

The aggregation of a-synuclein in dopaminergic neurons of the substantia nigra is a critical step in the pathogenesis of Parkinson's disease. We show that the antibiotic rifampicin inhibited a-synuclein fibrillation and disaggregated existing fibrils in a concentration-dependent manner. Size-exclusion chromatography data indicated that rifampicin stabilized a-synuclein as both a monomer and soluble oligomers comprised of partially folded a-synuclein. Experiments using aged samples of rifampicin indicated that the most active species in inhibiting fibrillation and disaggregating fibrils is an oxidation product of rifampicin, which was confirmed in experiments under anaerobic conditions. These results indicate that rifampicin-mediated inhibition of a-synuclein fibrillation and disaggregation of fibrils involves preferential stabilization of monomeric and soluble oligomeric forms, and that rifampicin potentially may have therapeutic application for Parkinson's disease.

引用

页码：1513 / 1521

页数：9

共 51 条

[1]

Ackers G K, 1970, Adv Protein Chem, V24, P343, DOI 10.1016/S0065-3233(08)60245-4

[2]

CHUI DH, 1994, AM J PATHOL, V145, P771

[3] Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct [J].

Conway, KA ;

Rochet, JC ;

Bieganski, RM ;

Lansbury, PT .

SCIENCE, 2001, 294 (5545) :1346-1349

[4] USE OF HIGH-SPEED SIZE-EXCLUSION CHROMATOGRAPHY FOR THE STUDY OF PROTEIN FOLDING AND STABILITY [J].

CORBETT, RJT ;

ROCHE, RS .

BIOCHEMISTRY, 1984, 23 (08) :1888-1894

[5] Annular α-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes [J].

Ding, TT ;

Lee, SJ ;

Rochet, JC ;

Lansbury, PT .

BIOCHEMISTRY, 2002, 41 (32) :10209-10217

[6] Intrinsically disordered protein [J].

Dunker, AK ;

Lawson, JD ;

Brown, CJ ;

Williams, RM ;

Romero, P ;

Oh, JS ;

Oldfield, CJ ;

Campen, AM ;

Ratliff, CR ;

Hipps, KW ;

Ausio, J ;

Nissen, MS ;

Reeves, R ;

Kang, CH ;

Kissinger, CR ;

Bailey, RW ;

Griswold, MD ;

Chiu, M ;

Garner, EC ;

Obradovic, Z .

JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 2001, 19 (01) :26-59

[7] Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils [J].

El-Agnaf, OMA ;

Nagala, S ;

Patel, BP ;

Austen, BM .

JOURNAL OF MOLECULAR BIOLOGY, 2001, 310 (01) :157-168

[8] Conformational properties of α-synuclein in its free and lipid-associated states [J].

Eliezer, D ;

Kutluay, E ;

Bussell, R ;

Browne, G .

JOURNAL OF MOLECULAR BIOLOGY, 2001, 307 (04) :1061-1073

[9] No effect of anti-leprosy drugs in the prevention of Alzheimer's disease and β-amyloid neurotoxicity [J].

Endoh, M ;

Kunishita, T ;

Tabira, T .

JOURNAL OF THE NEUROLOGICAL SCIENCES, 1999, 165 (01) :28-30

[10] Protein aggregation: folding aggregates, inclusion bodies and amyloid [J].

Fink, AL .

FOLDING & DESIGN, 1998, 3 (01) :R9-R23

← 1 2 3 4 5 6 →