Objective: We aimed to investigate the temporal and spatial evolution of immunoproteasome in the central nervous system (CNS) during PD pathogenesis using mouse model.

Background: Recent studies suggested that immune responses play important roles in Parkinson’s Disease (PD) pathogenesis beside the main hallmarks such as dopaminergic neuron loss and pathological form of α-Synuclein accumulation. Therefore, the immunoproteasome – a subtype of the proteasome among the ubiquitin-proteasomal system – implicated in both immune reactions and protein degradation, may bridge these features.

Method: For this study, we used αSyn preformed fibrils (PFF)-injected PD mouse model. The injected mice were sacrificed at 14, 30, 120, and 150 days after intrastriatal PFF injection, followed by harvesting the brain. The temporal expression of immunoproteasome subunits – PSMB8, PSMB9, and PSMB10 – was evaluated at 5 timepoints (including non-injected mice) through western blot, while the spatial changes of immunoproteasome were indicated by Immunofluorescences.

Results: Our study is the first to report the different expressions of immunoproteasome subunits during the progression of PD. We found that the expression of PSMB8, PSMB9 subunits increased continuously after PFF injection and reached statistical significance at 120-day post injection (dpi) and 150 dpi, respectively (p < 0.02). Meanwhile, PSMB10 reached a peak at 14 dpi and decreased afterward. And PSMB10 was expressed in TH positive dopaminergic neuron of substantia nigra, while PSMB8 and PSMB9 appeared abundantly in the striatum. In addition, all catalytic subunits were expressed in other brain regions beyond the nigrostriatal pathway, including somatosensory cortex, piriform cortex, hippocampus, which are well correlated with the regions of p-α-Synuclein accumulation.

Conclusion: Our study reveals clear alterations of immunoproteasome in the CNS of a PD mouse model, with distinct catalytic subunits showing different temporal and spatial contributions. These findings shed light on the potential role of immunoproteasome in the pathogenesis of PD and suggest that it may be a therapeutic target for the disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/distinct-temporal-and-spatial-alteration-of-immunoproteasome-in-parkinsons-disease-pathogenesis/