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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

DISEASE(S): Neurodevelopmental Delay

SUBMITTER: Amélie Bosc-Rosati

LAB HEAD: Odile Schiltz

PROVIDER: PXD058728 | Pride | 2025-08-04

REPOSITORIES: Pride

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			Action	DRS
	ABR_240212_PSMC5_MutvsMutvsControls_MCP21_IP.zip	Other
	ABR_240212_PSMC5vsControls_TotalLysate.zip	Other
	IP_MCP21_PSMC5_BLG1_6851.d.zip	Other
	IP_MCP21_PSMC5_BLG2_6852.d.zip	Other
	IP_MCP21_PSMC5_BLG3_6853.d.zip	Other

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