α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease

被引：370

作者：

Ludtmann, Marthe H. R. ^{[1
,2
]}

Angelova, Plamena R. ^{[1
]}

Horrocks, Mathew H. ^{[3
,4
,5
]}

Choi, Minee L. ^{[6
,7
]}

Rodrigues, Margarida ^{[3
]}

Baev, Artyom Y. ^{[8
]}

Berezhnov, Alexey V. ^{[9
]}

Yao, Zhi ^{[6
,7
]}

Little, Daniel

Banushi, Blerida

Al-Menhali, Afnan Saleh ^{[11
]}

Ranasinghe, Rohan T. ^{[3
]}

Whiten, Daniel R. ^{[3
,10
]}

Yapom, Ratsuda ^{[10
,12
]}

Dolt, Karamjit Singh ^{[12
]}

Devine, Michael J. ^{[10
,13
]}

Gissen, Paul ^{[10
]}

Kunath, Tilo ^{[12
]}

Jaganjac, Morana ^{[11
]}

Pavlov, Evgeny V. ^{[14
]}

Klenerman, David ^{[3
,15
]}

Abramov, Andrey Y. ^{[1
]}

Gandhi, Sonia ^{[6
,7
]}

机构：

[1] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[2] Royal Vet Coll, 4 Royal Coll St, London NW1 0TU, England

[3] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England

[4] Univ Edinburgh, EaStCHEM Sch Chem, David Brewster Rd, Edinburgh EH9 3FJ, Midlothian, Scotland

[5] Univ Edinburgh, UK Dementia Res Inst, Edinburgh, Midlothian, Scotland

[6] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Queen Sq, London WC1N 3BG, England

[7] Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England

[8] Educ Expt Ctr High Technol, Lab Biophys & Biochem, Tashkent, Uzbekistan

[9] Russian Acad Sci, Inst Cell Biophys, Pushchino 142290, Russia

[10] UCL, MRC, Lab Mol Cell Biol, Gower St, London WC1E 6BT, England

[11] Antidoping Lab Qatar, Toxicol & Multipurpose Dept, Sport City Rd,POB 27775, Doha, Qatar

[12] Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC,Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

[13] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England

[14] NYU, Coll Dent, Dept Basic Sci, New York, NY 10010 USA

[15] Univ Cambridge, UK Dementia Res Inst, Cambridge CB2 0XY, England

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金;

关键词：

PLURIPOTENT STEM-CELLS; OXIDATIVE STRESS; SUPERRESOLUTION MICROSCOPY; METHIONINE OXIDATION; REDOX REGULATION; DNA-PAINT; PROTEINS; CA2+; TRIPLICATION; MITOCHONDRIA;

D O I：

10.1038/s41467-018-04422-2

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：

Protein aggregation causes a-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric alpha-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric alpha-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate alpha-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of alpha-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.

引用

页数：16

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