WD repeat-containing protein 26

WDR26 is a WD repeat-containing scaffolding protein that functions as a G-beta-like protein involved in cell signal transduction (UniProt: Q9H7D7). It serves multiple regulatory roles, including acting as a negative regulator of MAPK signaling and the canonical Wnt pathway, coordinating PI3K/AKT-driven cell growth, and protecting cells from oxidative stress-induced apoptosis through AP-1 downregulation and inhibition of cytochrome c release. Additionally, WDR26 functions as a core component of the CTLH E3 ubiquitin-protein ligase complex, which mediates proteasomal degradation of the HBP1 transcription factor.

Mutations in WDR26 are associated with Skraban-Deardorff syndrome (SKDEAS), an autosomal dominant neurodevelopmental disorder characterized by psychomotor developmental delay, intellectual disability, seizures, and facial dysmorphism (UniProt: Q9H7D7). The protein's cytoprotective functions and involvement in fundamental signaling pathways implicate it in cellular stress responses.

In Alzheimer's Disease, WDR26 is downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.43 across subcellular fractions (Chaparral AD proteomics). This downregulation may compromise cellular protective mechanisms against oxidative stress and apoptosis relevant to AD pathogenesis.