N-acetylation of α-synuclein enhances synaptic vesicle clustering mediated by α-synuclein and lysophosphatidylcholine
Previously, we reported that α-synuclein (α-syn) clusters synaptic vesicles (SV) Diao et al., 2013, and neutral phospholipid lysophosphatidylcholine (LPC) can mediate this clustering Lai et al., 2023. Meanwhile, post-translational modifications (PTMs) of 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. 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. N-acetylation in our work is shown to fine-tune the interaction between α-syn and LPC, mediating α-syn’s role in synaptic vesicle clustering.
Authors
- Yaoyang Zhang (ORCID: https://orcid.org/0000-0001-5363-9834)
- Jacqueline Burré (ORCID: https://orcid.org/0000-0001-8968-248X)
- Chunyu Zhao (ORCID: https://orcid.org/0000-0003-0168-2130)
- Jiali Qiang (ORCID: https://orcid.org/0000-0001-6108-498X)
- Jinge Gu (ORCID: https://orcid.org/0000-0001-5219-5821)
- Zhenying Liu (ORCID: https://orcid.org/0000-0002-0035-7486)
- Chuchu Wang (ORCID: https://orcid.org/0000-0003-2015-7331)
- Jiajie Diao (ORCID: https://orcid.org/0000-0003-4288-3203)
- Cong Liu (ORCID: https://orcid.org/0000-0003-3425-6672)
- Dan Li (ORCID: https://orcid.org/0000-0002-1609-1539)
- Shengnan Zhang (ORCID: https://orcid.org/0000-0003-1051-7196)
- Xiao Hu
Institutions
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Cornell University (US)
- MIND Research Institute (US)
- Shanghai Institute of Organic Chemistry (CN)
- University of Chinese Academy of Sciences (CN)
- Weill Cornell Medicine (US)
- University of Cincinnati Medical Center (US)
- Stanford University (US)
Publication Details
- Journal
- eLife
- Published
- 2024-12-27
- DOI
- https://doi.org/10.7554/elife.97228.3
- Citations
- 6
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.21
Funders
- 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