Pathological role of immunoproteasome PSMB8 in Parkinson's disease: a link between α-synuclein aggregation and immune activation

Abstract

Background Parkinson's disease (PD) is characterised by alpha-synuclein accumulation and progressive neurodegeneration, with immune activation recognised as a key contributor. The immunoproteasome (IP), particularly its catalytic subunit PSMB8, plays dual roles in proteostasis and immune regulation, yet has an unclear role in synucleinopathies. Methods A total of 232 blood samples from patients with synucleinopathies (PD, multiple system atrophy [MSA], and rapid eye movement [REM] sleep behaviour disorder [RBD]), and healthy individuals were analysed for IP expression/activity in peripheral blood mononuclear cells (PBMCs) and neuronal extracellular vesicles (NEVs), and effects of IP inhibition using flow cytometry. Post-mortem human substantia nigra was examined for spatial distribution of PSMB8. The PD mouse model and human dopaminergic neuron models, combined with transcriptomic analysis, were used to investigate IP changes and inhibition effects. Findings Consistent upregulation of PSMB8 mRNA and protein was found in PBMCs and NEVs from people with PD, and MSA. This was recapitulated across multiple experimental models, including dopaminergic neurons treated with rotenone, carrying the SNCA-A53T, overexpressing alpha-synuclein, or exposed to alpha-synuclein preformed fibrils (PFF), as well as PFF-injected mice model. In human PD substantia nigra, PSMB8 was enriched in the core of mature Lewy bodies, revealing its involvement in synucleinopathies. Pharmacological inhibition of PSMB8 reduced alpha-synuclein accumulation and apoptosis in PD dopaminergic cell model, and decreased CD8+ T cells in PBMCs derived from patients with PD. Notably, alpha-synuclein clearance did not align with proteasomal or autophagy-lysosomal pathways, but instead correlated with non-proteasomal trypsin-like activity. In the CD8+ T cell-dopaminergic neuron co-culture model that mimics T cell mediated neuronal cytotoxicity, PSMB8 inhibition further improved neuronal survival, lowered intracellular alpha-synuclein levels, and attenuated CD8+ T cell degranulation, linking neuronal alpha-synuclein burden to immune-mediated toxicity. Interpretation These findings identify PSMB8 as a key molecular link between protein aggregation and immune dysregulation in PD, supporting its potential as a therapeutic target for synucleinopathies. Funding This research was funded by the Ministry of Education (RS-2023-00246655), the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-00265159), the Korea government (MSIT) (2022R1A2C2091254; RS-2023-00223501). Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).