NeuralCipher Research overview
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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.
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