26S proteasome regulatory subunit 8

PSMC5 (26S proteasome regulatory subunit 8) is an AAA-ATPase component of the 26S proteasome complex that catalyzes ATP-dependent degradation of ubiquitinated proteins. It functions as part of the heterohexameric regulatory ring that unfolds misfolded or damaged proteins for translocation into the proteolytic chamber and degradation into peptides (UniProt: P62195). This complex is essential for protein homeostasis and participates in cell cycle progression, apoptosis, and DNA damage repair.

The protein is part of the core proteasomal machinery, which maintains cellular protein quality control across all tissues and is particularly critical in neurons due to their reliance on precise protein turnover and clearance of aggregation-prone species.

PSMC5 is downregulated in Alzheimer's disease brain tissue. Post-mortem human AD brain samples showed reduced PSMC5 expression compared to age-matched controls (mean log2FC: −0.27; Chaparral AD proteomics). This reduction may compromise proteasomal capacity, potentially impairing clearance of amyloid-β and tau aggregates that accumulate in AD pathology. Impaired proteasomal function is hypothesized to contribute to the protein aggregation and neurodegeneration characteristic of AD.