Publication Date

11-26-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-65556-8

PMID

41298377

PMCID

PMC12658096

PubMedCentral® Posted Date

11-26-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.

Keywords

Proteasome Endopeptidase Complex, Animals, Humans, Neurodevelopmental Disorders, Neurons, Male, Drosophila melanogaster, Female, Mitochondria, ATPases Associated with Diverse Cellular Activities, Adenosine Triphosphatases, Drosophila Proteins, Child, Neurodevelopmental disorders, Translational research, Neurodevelopmental disorders

Published Open-Access

yes

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