Chromogranin A promotes the pathological conversion of α-synuclein at the synapse in Parkinson’s disease
α-Synuclein (αSyn) aggregation is a prominent hallmark of Parkinson's disease (PD), yet the initial cellular mechanisms are not well understood. In this study, we show that a single day of αSyn preformed fibril (PFF) administration leads to prominent localization of phosphorylated αSyn (p-αSyn) within the pre-synapse of primary neurons. Overexpressing chromogranin A (CgA), which is found in large dense-core vesicles (LDCVs), enhances αSyn aggregation in various neuronal and PD mouse models. Subsequently, by incubating αSyn with CgA, we create a unique strain of fibrils displaying smaller length, stronger resistance to proteolytic digestion, and higher amyloidogenic properties compared to conventional αSyn fibrils. Additionally, CgA knockout alleviates dendritic spine loss and synaptic dysfunction induced by αSyn PFF and slows down the spread of pathological inclusions in vivo. Collectively, our findings demonstrate how the intra-vesicular matrix protein CgA triggers and facilitates early seeding events leading to subsequent toxicity caused by αSyn pathology.
Authors
- Renzheng Li
- Linlin Zhou (ORCID: https://orcid.org/0009-0009-0705-0725)
- Weixian Kong
- Yu Liu (ORCID: https://orcid.org/0000-0002-1806-6011)
- Ke Xu (ORCID: https://orcid.org/0000-0003-2459-5064)
- Virginia Man-Yee Lee
- Zhenyu Cai (ORCID: https://orcid.org/0000-0003-2230-6150)
- Yazhong Ji (ORCID: https://orcid.org/0000-0002-4395-0378)
- Jialin Zheng (ORCID: https://orcid.org/0000-0003-2286-0151)
- Yong Bi
- Long Guo (ORCID: https://orcid.org/0000-0001-5114-4045)
- Qihui Wu (ORCID: https://orcid.org/0000-0001-7154-7765)
- Guo Xiaoyang
- Chengjie Li
- Li Cui (ORCID: https://orcid.org/0000-0002-0924-7283)
- Yihan Liu (ORCID: https://orcid.org/0000-0001-9094-0693)
- Pu Ai
- Feipeng Zhu (ORCID: https://orcid.org/0000-0002-7885-7544)
- Jiale Han (ORCID: https://orcid.org/0009-0004-6895-0130)
- Jinwen Jiang
- Yuwei Wang (ORCID: https://orcid.org/0009-0003-0414-4490)
Institutions
- Tongji University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Stomatological Hospital (CN)
- Institute of Genetics and Developmental Biology (CN)
- Shanghai Pulmonary Hospital (CN)
- Shanghai East Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- Shanghai University of Medicine and Health Sciences (CN)
- Institute on Aging (US)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116562
- Citations
- 1
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.39