首页|Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

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Accumulation of aggregated α-synuclein(α-syn)in Lewy bodies is the pathological hallmark of Parkinson's disease(PD).Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism.The role of α-syn's lipid interactions in its function and aggregation is recognized,yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear.Here,we found that α-syn shows a preference for binding to lysophospholipids(LPLs),particularly targeting lysophosphatidylcholine(LPC)without relying on electrostatic interactions.LPC is capable of maintaining α-syn in a compact conformation,significantly reducing its propensity to aggregate both in vitro and within cellular environments.Conversely,a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation.Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation,and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

α-synucleinParkinson's diseaselysophosphatidylcholineaggregation

Chunyu Zhao、Jia Tu、Chuchu Wang、Wenbin Liu、Jinge Gu、Yandong Yin、Shengnan Zhang、Dan Li、Jiajie Diao、Zheng-Jiang Zhu、Cong Liu

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Interdisciplinary Research Center on Biology and Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 201210,China

University of Chinese Academy of Sciences,Beijing 100049,China

Bio-X Institutes,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders,Ministry of Education,Shanghai Jiao Tong University,Shanghai 200030,China

Zhangjiang Institute for Advanced Study,Shanghai Jiao Tong University,Shanghai 200040,China

Department of Cancer Biology,University of Cincinnati College of Medicine,Cincinnati,OH 45267,USA

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Major State Basic Research Development ProgramNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of Chinascience and Technology Commission of Shanghai Municipality(STCSM)Shanghai Pilot Program for Basic Research—Chinese Academy of Sciences,Shanghai BranchCAS Project for Young Scientists in Basic ResearchShanghai Municipal Science and Technology Major ProjectShanghai Basic Research Pioneer Project

2019YFE01206002018YFA08009028218810132171236923533023217068322JC1410400CYJ-SHFY-2022-005YSBR-095

2024

10.1093/nsr/nwae182

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ISSN：
年,卷(期)：2024.11(6)