1. Academic Validation
  2. Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease

Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease

  • Redox Biol. 2021 Nov;47:102167. doi: 10.1016/j.redox.2021.102167.
Mingxia Bi 1 Xixun Du 1 Xue Xiao 1 Yingying Dai 1 Qian Jiao 1 Xi Chen 1 Lingqiang Zhang 2 Hong Jiang 3
Affiliations

Affiliations

  • 1 Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
  • 2 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 3 Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China. Electronic address: hongjiang@qdu.edu.cn.
Abstract

Aberrant α-synuclein (α-Syn) accumulation resulting from Proteasome dysfunction is considered as a prominent factor to initiate and aggravate the neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S Proteasome in proteostasis imbalance has been widely accepted, our knowledge about the regulation of immunoproteasome function and its potential role in α-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially β-ring formation mediated by the only well-known chaperone Proteasome maturation protein (POMP). Here, we identified that α-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated α-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by β5i overexpression. Mechanistically, α-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome β subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of α-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing α-Syn accumulation and neurodegeneration, which might open up a new perspective for the implication of immunoproteasome in PD and provide approaches of manipulating immunoproteasome assembly for therapeutic purposes.

Keywords

Immunoproteasome; NRF2; POMP; Parkinson's disease; α-synuclein.

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