WD repeat domain phosphoinositide-interacting protein 4 (WDR45)

WD repeat domain phosphoinositide-interacting protein 4 (WDR45; also known as WIPI4) is an evolutionarily conserved member of the WD repeat protein family characterized by a seven-bladed beta-propeller structure. It acts as a scaffold for protein-protein interactions in the assembly of autophagy machinery, promoting autophagosome formation and elongation and ensuring the degradation and recycling of unwanted proteins and organelles. WDR45 binds phosphoinositides via a conserved motif, facilitating recruitment to membranes where autophagosomes initiate. It also participates directly in regulating stress granule disassembly dynamics under cellular stress conditions. In humans, loss-of-function mutations in the WDR45 gene cause beta-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA) characterized by early developmental delay, epilepsy, progressive intellectual decline, movement disorders, and iron accumulation in the brain visible on MRI. WDR45 dysfunction leads to impaired autophagy and ferritinophagy, causing cellular iron overload, oxidative stress, and mitochondrial dysfunction. Currently, WDR45 is a disease gene but is not a direct pharmacological target for any approved therapies.

Other names

WIPI4WD repeat domain 45WD repeat-containing protein 45WD45 repeat protein interacting with phosphoinositides 4WD repeat domain, X-linked 1JM5NBIA4NBIA5WDRX1WDRXI4WIPI-4

Not applicable (no known direct WDR45-targeting drugs). Mechanistically, loss-of-function causes impaired autophagy, altered stress granule dynamics, and intracellular iron overload, but these are not targeted by current therapeutic agents.