257: PSMC5: proteasomes, immunity and neurodevelopment

Küry S et al., Nature Communications, doi:10.1038/s41467-025-65556-8 - This study describes 26 distinct PSMC5 variants in 44 individuals and demonstrates that PSMC5 loss impairs proteasome function, driving proteotoxic stress, mitochondrial and lipid dysregulation, sterile type I interferon activation, and neurodevelopmental deficits. Key terms: PSMC5, proteasome, neurodevelopment, interferon, mitophagy.

Study Highlights:
Twenty-six distinct PSMC5 variants were identified in 44 affected individuals, mostly heterozygous and de novo, clustering in the AAA+ ATPase domain and predicted to be pathogenic. Functional assays and patient T cells show that many variants perturb PSMC5 incorporation into 26S proteasomes, reduce proteasome activity, and increase ubiquitin-positive aggregates and aggresomes. Multi-omics of patient T cells revealed disrupted mitochondrial proteostasis with increased mitophagy, altered glycerophospholipid profiles and impaired ribosome biogenesis. Neuronal models and Drosophila demonstrate reduced excitatory synapses, E/I imbalance, impaired neuritogenesis, deficits in reversal learning and compromised NPC differentiation, while ISR kinases PKR and GCN2 plus cGAS-STING and JAK pathways mediate a spontaneous type I IFN response that can be pharmacologically reduced.

Conclusion:
PSMC5 variants cause proteasome loss-of-function that links proteotoxic stress to innate immune activation and impaired neurogenesis, identifying ISR and JAK pathway components as potential therapeutic targets.

Music:
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Article title:
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

First author:
Küry S

Journal:
Nature Communications, doi:10.1038/s41467-025-65556-8

DOI:
10.1038/s41467-025-65556-8

Reference:
Küry S, Bézieau S, Ebstein F, et al. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nature Communications. 2025;16:10545. https://doi.org/10.1038/s41467-025-65556-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content describing PSMC5/UPS biology, variant effects, multi-model analyses (Drosophila, rat neurons, iPSC-derived NPCs), ISR and IFN signaling, lipid/mitophagy changes, synaptic balance, and therapeutic implications.
- transcript topics: PSMC5 and 26S proteasome function; PSMC5 variants and neurodevelopmental proteasomopathies; Proteotoxic stress and aggresome formation; Mitochondrial dysfunction and mitophagy; Lipid metabolism dysregulation; Integrated stress response (PKR/GCN2) and type I interferon signaling

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- 26 distinct PSMC5 variants identified in 44 individuals
- Variants cluster in the AAA+ ATPase domain; Arg325Trp recurring
- Loss of PSMC5 function impairs proteasome activity, causing proteotoxic stress and aggresome formation
- Mitophagy is increased and lipid metabolism is disrupted (50% increase in cholesterol esters; decreased glycerophospholipids)
- Transcriptomic/type I IFN signature elevated in patient T cells; ISR mediates IFN induction; PKR/GCN2 inhibitors reduce IFN scores; baricitinib (JAK inhibitor) also reduces IFN sco
- Arg325Trp variant impairs neural progenitor cell differentiation in iPSC models

QC result: Pass.