Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

Neurodevelopmental disorders (NDDs) are conditions that affect the development of the central nervous system, often identified during early childhood. These disorders include intellectual disability, communication disorders, autism spectrum disorders, and attention-deficit hyperactivity disorder (ADHD). Approximately 40% of NDDs are monogenic diseases, with at least 8% involving genes of the ubiquitin-proteasome system (UPS). This conserved proteolytic system plays a key role in protein homeostasis by degrading ubiquitin-tagged proteins. Among monogenic pathologies linked to the UPS, genetic variations directly affecting the 26S proteasome define a new subclass of NDDs known as neurodevelopmental proteasomopathies. The submitted data originate from an exhaustive study on several unique variants identified in the PSMC5 gene, which encodes the AAA-ATPase subunit PSMC5/Rpt6 of the 26S proteasome. Functional analyses conducted in this study revealed that these alterations lead to a loss of proteasome function, triggering a complex cellular program involving an inflammatory response and innate immunity remodeling. To further investigate these observations, gene expression was analyzed using NanoString on an autoimmune gene panel, revealing a type I interferon signature in the patients. These results were confirmed by 3'seq-RNA Profiling (3'SRP), which showed strong overexpression of genes in the type I interferon pathway, accompanied by transcriptional dysregulation involving alterations in innate immunity and inflammatory processes. The provided data thus confirm the central role of PSMC5 gene alterations in the pathogenesis of neurodevelopmental proteasomopathies.