PSMC5 encodes an AAA-ATPase subunit of the 26S proteasome's 19S regulatory particle, serving a critical role in ATP-dependent ubiquitin-proteasome degradation 1. As part of the heterohexameric ring, PSMC5 unfolds ubiquitinated target proteins for translocation into the proteolytic chamber and subsequent degradation, maintaining cellular protein homeostasis 2. This function is essential for numerous cellular processes including cell cycle progression, apoptosis, and DNA damage repair. PSMC5 variants cause neurodevelopmental proteasomopathies (NDD), a distinct category of neurodevelopmental disorders 1. Over 23 unique PSMC5 variants have been identified in syndromic NDD patients, with both overexpression and loss-of-function mutations impairing proteasome activity 13. Loss of PSMC5 function results in protein aggregation, abnormal innate immune signaling, impaired mitochondrial homeostasis, and disrupted lipid metabolism 1. Functionally, PSMC5 variants compromise synaptic balance, neuritogenesis, and learning capacity 3. PSMC5 insufficiency and specific mutations like P320R weaken the association between the 19S regulatory particle and 20S core particle, impairing overall proteasome function and activating apoptosis 2. PSMC5 variants also associate with proteasome-associated autoinflammatory syndromes (PRAAS) 4. Therapeutically, targeting integrated stress response kinases (PKR, GCN2) ameliorates immune dysregulation in affected cells 1, offering potential treatment avenues for neurodevelopmental proteasomopathies.