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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288665 | GEO | 2025/08/04

REPOSITORIES: GEO

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Project description:In eukaryotic cells, short-lived, regulatory and misfolded or denatured proteins are degraded by the ubiquitin–proteasome system (UPS), a highly regulated mechanism including the active marking of proteins for proteasomal degradation by ubiquitin. The UPS is critical in regulating proteostasis and dysfunctioning of this system has been implicated in diseases such as cancer and neurodegenerative disorders. We have investigated the effects of proteasome malfunctioning in Drosophila by monitoring the global proteome and ubiquitinome using SILAC proteomics. The proteasome was inactivated by either chemical inhibitors or by dsRNA mediated knockdown of specific proteasome subunit constituents. Upon proteasome perturbation both the global proteome and the ubiquitinome were remodeled to a great extent, albeit that the overall impact on the ubiquitinome was much more dramatic. The abundances of ~10% of all observable proteins were increased as a result of both de novo synthesis and of accumulation of ubiquitinated proteins. In the ubiquitinome analysis ~14,000 diGly peptides were identified and most of these could also be quantified. The far majority of diGly peptides showed increased levels, indicating that the pool of ubiquitinated proteins is highly dynamic. Interestingly, because of the high level of detail the ubiquitination dynamics of individual proteins could be explored. Several examples (e.g., Rps3 and H2B) will be discussed, in which different target lysine residues show either increased or decreased ubiquitination on the same protein, suggesting the occurrence of simultaneous and possibly functionally different ubiquitination events. In conclusion, the combination of quantitative proteomic methods with dsRNA mediated knockdown of individual subunits of the 26S proteasome offers a powerful tool to study the dynamics of the (modified) proteome upon perturbation of the UPS. This strategy opens up new avenues for the dissection of the mode of action of this cellular machinery, both under proteostasis and proteotoxic conditions.

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

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