Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models
Rui Han, … , Xiao-Jiang Li, Weili Yang
Rui Han, … , Xiao-Jiang Li, Weili Yang
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(20):e179633. https://doi.org/10.1172/JCI179633.
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Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models

Abstract

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

Rui Han, Qi Wang, Xin Xiong, Xiusheng Chen, Zhuchi Tu, Bang Li, Fei Zhang, Chunyu Chen, Mingtian Pan, Ting Xu, Laiqiang Chen, Zhifu Wang, Yanting Liu, Dajian He, Xiangyu Guo, Feng He, Peng Wu, Peng Yin, Yunbo Liu, Xiaoxin Yan, Shihua Li, Xiao-Jiang Li, Weili Yang

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Figure 7

Reduced parkin phosphorylation and increased pS129-α-syn in the brains of PD monkey models and patients.

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Reduced parkin phosphorylation and increased pS129-α-syn in the brains o...
(A) Low magnification of a human brain section containing the SN for examination. (B) In postmortem brains of 2 normal individuals (C1 and C2) and sporadic PD patients (PD-1 and PD-2), pS65-parkin expression is reduced in the SN neurons in PD patient brains. Scale bar: 2 mm. (C) Quantification of the relative expression levels of ubiquitin and pS65-parkin in B. Two human brain samples for each group were used for quantification: 2 PD cases (PD-1: 77 years, female; and PD-2: 55 years, female) and 2 control cases (C-1: 48 years, female; and C-2: 54 years, male). Representative immunostaining images are from multiple technical replicates of 2 human brains. (D) Reduced pS65-parkin (S65) and increased pS129-α-syn occurred in the SN of PINK1 mutant monkey (M6, 3 years old) (left panel). Ratios of pS65-parkin to total parkin or pS129-α-syn to total α-syn or vinculin (n = 4 independent experiments each group) are also presented (right panel). (E) Representative images of reduced pS65-parkin and increased pS129-a-syn occurred in the SN of a 10-year-old monkey that was injected with AAV9-PINK1 gRNA/Cas9. (F) Representative images of PINK1 reduction by AAV9-PINK1 gRNA/Cas9 injection led to more pS129-α-syn accumulation in the SN of an older (22 years old) monkey than a younger (10 years old) monkey. (G) High-magnification micrographs showing cytoplasmic pS129-α-syn accumulation and aggregates. Arrows indicate cytoplasmic labeling of pS129-α-syn. In E–G, representative immunostaining images are from multiple technical replicates of 3 WT monkey brains.