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

Aberrant alpha-synuclein (alpha-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 alpha-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially beta-ring formation mediated by the only well-known chaperone proteasome maturation protein (POMP). Here, we identified that alpha-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated alpha-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by beta 5i overexpression. Mechanistically, alpha-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome beta subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of a-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing alpha-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.

Automated summary

The overexpression of alpha-Syn was found to reduce immunoproteasome function, exacerbating phosphorylation and aggregation, ultimately leading to neurodegeneration in Parkinson's Disease.