Objective: To determine if the immunoproteasome (IP) subunit PSMB8 serves as a pathological link between α-synuclein aggregation and cytotoxic immune responses in Parkinson’s disease (PD).

Background: Chronic immune activation and protein misfolding are core pillars of PD. The IP is a specialized proteasome variant induced by stress, but its specific role in mediating neuro-immune crosstalk in synucleinopathies remains poorly understood.

Method: We performed a comprehensive multimodal analysis using:

Large-scale clinical cohort: Analysis of 232 peripheral blood samples from patients with PD (n=101), Multiple System Atrophy (MSA, n=41), REM Sleep Behavior Disorder (RBD, n=36), and healthy controls. We assessed IP mRNA/protein expression in PBMCs and neuronal extracellular vesicles.

Human post-mortem and in vivo model: Spatial distribution of PSMB8 was mapped in human substantia nigra and validated in a unilateral striatal PFF-injected mouse model.

Advanced cell models: We reanalyzed public scRNA-seq data from iPSC-derived SNCA-A53T and rotenone-treated dopaminergic (DA) neurons. Furthermore, LUHMES-derived DA neurons (overexpressing α-synuclein + PFF) were treated with the PSMB8 inhibitor ONX-0914 to assess effects on proteostasis.

Neuro-Immune co-culture: A novel system was developed by co-culturing patient-derived CD8+ T-cells with PD-model DA neurons. We specifically tested the effects of IP inhibition by treating both neurons and CD8+ T-cells with ONX-0914 to distinguish between cell-autonomous and non-cell-autonomous protection.

Results: PSMB8 mRNA and protein were significantly upregulated across the clinical spectrum. In human PD brains, PSMB8 was specifically sequestered in the central core of mature Lewy bodies. Pharmacological inhibition of PSMB8 with ONX-0914 reduced α-synuclein accumulation and apoptosis in DA neurons. This clearance correlated with an increase in non-proteasomal trypsin-like activity rather than traditional autophagy. In co-culture, PSMB8 inhibition improved neuronal survival and attenuated T-cell degranulation, demonstrating that reducing neuronal α-synuclein burden directly lowers susceptibility to immune attack.

Conclusion:

Our findings establish PSMB8 as a systemic feature of synucleinopathies. Targeting PSMB8 provides a dual therapeutic benefit by enhancing α-synuclein clearance and dampening cytotoxic T-cell responses.​​​​​​​

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-the-immunoproteasome-psmb8-a-dual-strategy-to-enhance-%ce%b1-synuclein-clearance-and-mitigate-cd8-t-cell-neurotoxicity-in-parkinsons-disease/