期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2109617119
关键词
Parkinson's disease; alpha-synuclein; phosphorylation
资金
- Qatar Biomedical Research Institute [VR98]
- Alzheimer's Research UK Fellowship [ARUK-RF2018C-005]
- UK Medical Research Council [G0400074]
- National Institute for Health Research Newcastle Biomedical Research Centre
- Alzheimer's Society
- Alzheimer's Research UK as part of the Brains for Dementia Research Project
- Lundbeck Foundation [R223-2015-4222, R248-2016-2518]
The phosphorylation of alpha-synuclein at serine 129 inhibits fibril formation and appears to have a protective role in the aggregation process, which has implications for understanding the pathobiology of Lewy body disease.
alpha-Synuclein (alpha-syn) phosphorylation at serine 129 (pS129-alpha-syn) is substantially increased in Lewy body disease, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129-alpha-syn remains controversial, so we sought to identify when pS129 modification occurs during alpha-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129-alpha-syn inhibits alpha-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129-alpha-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129-alpha-syn (WT-alpha-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of alpha-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with alpha-syn preformed fibrils, and we observed aggregation of nonphosphorylated a-syn followed by later pS129-alpha-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated alpha-syn and disease duration. These findings suggest that pS129-alpha-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129-alpha-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129-alpha-syn as a measure of efficacy in clinical trials.
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