Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies
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PROVIDER: PRJNA1218815 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-08-04 | GSE288665 | GEO
Project description:Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5, which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
2025-08-04 | PXD058728 | Pride
Project description:Autophagy upregulation enhances the clearance of various neurotoxic proteins and ameliorates their toxicities in disease models. Thus, autophagy activators may have therapeutic utility. Here, we have identified the essential protein VCP/p97 as a target of the autophagy-inducing molecule SMER28, providing a mechanism for a molecule that has shown promising results in animal models of neurodegeneration. SMER28 stimulates VCP D1 ATPase activity to activate autophagy by enhancing interactions of PI3K complex components to increase PI(3)P production and consequent autophagosome formation. Interestingly, SMER28-mediated increase in VCP D1 ATPase activity also enhances degradation of short-lived misfolded and aggregate-prone proteins through the ubiquitin-proteasome system (UPS). We further show that another recently described activator of VCP induces autophagy and UPS flux in a comparable manner, providing additional evidence that targeting VCP D1 ATPase domain could be a useful approach for clearance of aggregate-prone proteins by both autophagy-lysosome and proteasomal routes.
2022-07-15 | PXD027750 | Pride
Project description:Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington’s disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome. Here we find that compounds that activate the D1 ATPase activity of VCP/p97 fulfill these requirements. Such effects are seen with small molecule VCP activators like SMER28, which activate autophagosome biogenesis by enhancing interactions of PI3K complex components to increase PI(3)P production, and also accelerate VCP-dependent proteasomal clearance of such substrates. Thus, this mode of VCP activation may be a very attractive target for many neurodegenerative diseases.
2022-07-15 | PXD034712 | Pride
Project description:Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. We sought to define this defect by expression analysis of cells lacking functional CSB, a SWI/SNF-like ATPase that is responsible for most CS cases.
2007-07-03 | E-GEOD-3407 | biostudies-arrayexpress
Project description:Plasma membrane H+-ATPase provides the driving force for light-induced stomatal opening. However, the mechanisms underlying the regulation of its activity remain unclear. Here, we showed that the phosphorylation of two Thr residues in the C-terminal autoinhibitory domain is crucial for H+-ATPase activation and stomatal opening. Our phosphoproteome analysis revealed that blue light induces the phosphorylation of Thr-881 within the C-terminal region I domain and penultimate Thr-948 in AUTOINHIBITED H+-ATPASE 1 (AHA1). The site-directed mutagenesis showed that both Thr phosphorylations are essential for H+ pumping and stomatal opening in response to blue light. The phosphorylation of Thr-948 is a prerequisite for the phosphorylation of Thr-881 by blue light. Furthermore, red-light-driven guard cell photosynthesis also caused Thr-881 phosphorylation, possibly contributing to red-light-dependent stomatal opening. Taken together, our findings provide mechanistic insights into H+-ATPase activation that exploits the ion transport across the plasma membrane and light signalling network in guard cells.
2023-12-25 | PXD039740 | JPOST Repository
Project description:Human neurodevelopmental samples
| PRJNA663321 | ENA
Project description:	Plasma membrane H+-ATPase provides the driving force for light-induced stomatal opening. However, the mechanisms underlying the regulation of its activity remain unclear. Here, we showed that the phosphorylation of two Thr residues in the C-terminal autoinhibitory domain is crucial for H+-ATPase activation and stomatal opening. Our phosphoproteome analysis revealed that blue light induces the phosphorylation of Thr-881 within the C-terminal region I domain and penultimate Thr-948 in AUTOINHIBITED H+-ATPASE 1 (AHA1). The site-directed mutagenesis showed that both Thr phosphorylations are essential for H+ pumping and stomatal opening in response to blue light. The phosphorylation of Thr-948 is a prerequisite for the phosphorylation of Thr-881 by blue light. Furthermore, red-light-driven guard cell photosynthesis also caused Thr-881 phosphorylation, possibly contributing to red-light-dependent stomatal opening. Taken together, our findings provide mechanistic insights into H+-ATPase activation that exploits the ion transport across the plasma membrane and light signalling network in guard cells.
2023-12-25 | PXD044476 | JPOST Repository
Project description:Involvement of cardiac glycosides targeting Na/K-ATPase in their inhibitory effects on c-Myc expression via its transcription, translation, and proteasomal degradation
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Project description:The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain mysterious. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed the "V-ATPase-autophagy axis". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that the V-ATPase-autophagy axis is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates the V-ATPase-autophagy axis via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide a clear explanation for the mutational activation of autophagy seen in follicular lymphoma patients.
2025-03-11 | GSE290977 | GEO