Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models
Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.
Authors
- Zhifu Wang
- Mingtian Pan
- Rui Han (ORCID: https://orcid.org/0000-0001-8856-3681)
- Xiusheng Chen
- Yunbo Liu (ORCID: https://orcid.org/0000-0003-2727-8515)
- Xiangyu Guo (ORCID: https://orcid.org/0000-0001-9699-8669)
- Xiao‐Xin Yan (ORCID: https://orcid.org/0000-0001-6654-982X)
- Laiqiang Chen
- Bang Li (ORCID: https://orcid.org/0000-0002-7254-6569)
- Peng Yin (ORCID: https://orcid.org/0000-0002-4811-6956)
- Peng Wu (ORCID: https://orcid.org/0000-0003-2676-508X)
- Qi Wang (ORCID: https://orcid.org/0000-0001-7626-676X)
- Chun‐Yu Chen (ORCID: https://orcid.org/0000-0001-7199-3271)
- Ting Xu (ORCID: https://orcid.org/0009-0002-7411-7669)
- Shihua Li (ORCID: https://orcid.org/0000-0003-1775-6536)
- Xiaojiang Li (ORCID: https://orcid.org/0009-0009-7217-6957)
- Yanting Liu (ORCID: https://orcid.org/0000-0002-9591-3042)
- Feng He (ORCID: https://orcid.org/0000-0002-7034-4285)
- Weili Yang
- Xin Xiong
- Dajian He
- Zhuchi Tu
- Fei Zhang (ORCID: https://orcid.org/0000-0001-6147-6131)
Institutions
- Central South University (CN)
- Jinan University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wuhan Institute of Bioengineering (CN)
- Institute of Laboratory Animal Science (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1172/jci179633
- Citations
- 22
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.12
Funders
- National Natural Science Foundation of China