N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine

Year: 2024

Type: article

Abstract: Post-translational modifications (PTMs) of α-synuclein (α-syn) such as acetylation and phosphorylation play important yet distinct roles in regulating α-syn conformation, membrane binding, and amyloid aggregation. However, how PTMs regulate α-syn function in presynaptic terminals remains unclear. Previously, we reported that α-syn clusters synaptic vesicles (SV) 1 , and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering 2 . Here, based on our previous findings, we further demonstrate that N-terminal acetylation, which occurs under physiological conditions and is irreversible in mammalian cells, significantly enhances the functional activity of α-syn in clustering SVs. Mechanistic studies reveal that this enhancement is caused by the N-acetylation-promoted insertion of α-syn’s N-terminus and increased intermolecular interactions on the LPC-containing membrane. Our work demonstrates that N-acetylation fine-tunes α-syn–LPC interaction for mediating α-syn’s function in SV clustering.

Source: eLife

DOI: 10.7554/elife.97228.3

Authors: Chuchu Wang, Chunyu Zhao, Xiao Hu, Jiali Qiang, Zhenying Liu, Jinge Gu, Shengnan Zhang, Dan Li, Yaoyang Zhang, Jacqueline Burré, Jiajie Diao, Cong Liu

Institutions: Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Stanford University, University of Cincinnati, Shanghai Jiao Tong University, Cornell University, Weill Cornell Medicine

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,500

Funders: National Science Foundation, Michael J. Fox Foundation for Parkinson's Research, National Natural Science Foundation of China, Chinese Academy of Sciences, Science and Technology Commission of Shanghai Municipality, Chinese Academy of Sciences, Shanghai Branch, National Institutes of Health, National Key Research and Development Program of China, National Institute of Neurological Disorders and Stroke

OpenAlex ID: W4405835976