Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
    • 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.
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    • Contributed Indexing:
      Keywords: Aging; Neuroscience; Parkinson disease
    • Accession Number:
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
      EC 2.3.2.27 (parkin protein)
      0 (alpha-Synuclein)
      EC 2.7.11.1 (PTEN-induced putative kinase)
      EC 2.7.- (Protein Kinases)
    • Publication Date:
      Date Created: 20241015 Date Completed: 20241015 Latest Revision: 20241018
    • Publication Date:
      20241018
    • Accession Number:
      PMC11473153
    • Accession Number:
      10.1172/JCI179633
    • Accession Number:
      39403921