한빛사논문
- 조회1,716
UCL Queen Square Institute of Neurology, The Francis Crick Institute, University College London
Plamena R. Angelova1, Minee L. Choi1,2, Alexey V. Berezhnov3,4, Mathew H. Horrocks5,6, Craig D. Hughes6, Suman De6,7, Margarida Rodrigues6,7, Ratsuda Yapom8, Daniel Little9,10, Karamjit S. Dolt8, Tilo Kunath8, Michael J. Devine9, Paul Gissen9,10, Mikhail S. Shchepinov11, Sergiy Sylantyev1,12, Evgeny V. Pavlov13, David Klenerman6,7, Andrey Y. Abramov1,4,*, Sonia Gandhi1,2,*
1 UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK
2 The Francis Crick Institute, London, UK
3 Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino 142290, Russia
4 Orel State University, Orel, Russia
5 EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK
6 Department of Chemistry, University of Cambridge, Cambridge, UK
7 Dementia Research institute at University of Cambridge, Cambridge, UK
8 MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
9 MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, UK
10 NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
11 Retrotope Inc., Los Altos, CA 94022, USA
12 Rowett Institute, University of Aberdeen, Ashgrove Rd West, Aberdeen AB25 2ZD, UK
13 College of Dentistry, New York University, New York, NY, USA
These authors contributed equally: Plamena R. Angelova, Minee L. Choi
These authors jointly supervised this work: Andrey Y. Abramov, Sonia Gandhi
*Corresponding authors
Abstract
Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.
논문정보
- Research article
- 2020년 10월 (BRIC 등록일 2020-11-13)
- 국외 연구진
- 생명과학 > 신경생물학
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