ArticleEBioMedicine2025
Pathological role of immunoproteasome PSMB8 in Parkinson's disease: a link between α-synuclein aggregation and immune activation.
Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine synthesis.The Journal of clinical investigation · 2026Article
- Spatial Single-Cell Proteomics Reveals Molecular Trajectories Of Tangle-Bearing Neurons In Alzheimer's Disease.bioRxiv : the preprint server for biology · 2026Article
- The immunoproteasome as a neuroimmune hub in the central nervous system: from proteostasis stress to inflammatory pathology.Journal of neuroinflammation · 2026Review
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8 authors.
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Abstract
backgroundParkinson's disease (PD) is characterised by α-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.
methodsA 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.
findingsConsistent 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 α-synuclein, or exposed to α-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 α-synuclein accumulation and apoptosis in PD dopaminergic cell model, and decreased CD8
interpretationThese 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.
fundingThis 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).
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