Wdr45-KO Mouse

Wdr45, also known as WIPI4, is a WD-repeat β-propeller protein belonging to the WIPI (WD repeat domain, phosphoinositide interacting) family. It is located on the X-chromosome and plays a role in pathways potentially related to macroautophagy, mitochondrial function, endoplasmic reticulum (ER) homeostasis, and iron homeostasis [1].

Constitutive wdr45 knockout (KO) mice showed cognitive impairments, abnormal synaptic transmission, and lesions in several brain regions. Aged KO mice had neuron loss in the prefrontal cortex and basal ganglion, and increased apoptosis in the prefrontal cortex. Quantitative proteomic analysis of KO mice revealed accumulation of ER proteins, leading to increased ER stress, impaired ER quality control, elevated unfolded protein response (UPR) through ERN1/IRE1 or EIF2AK3/PERK pathway, and ultimately neuronal apoptosis [2]. WDR45-knockout SH-SY5Y neuroblastoma cell line showed that non-TF-bound iron pathway mediated iron accumulation, and loss of WDR45 led to defects in ferritinophagy, contributing to iron accumulation in mitochondria, accompanied by impaired mitochondrial respiration, elevated reactive oxygen species, and increased cell death [3].

In conclusion, Wdr45 is crucial for maintaining normal cellular functions related to autophagy, ER homeostasis, and iron metabolism. Studies using KO mouse models and cell lines have provided insights into its role in neurodegenerative diseases such as β-propeller protein-associated neurodegeneration (BPAN), where Wdr45 deficiency may lead to a cascade of cellular malfunctions contributing to the disease pathophysiology [1,2,3].