Autophagy involves the enclosure of cytoplasmic material in a double-membrane autophagosome and its subsequent delivery to the lysosome for degradation. It plays an essential role in maintaining metabolic homeostasis under physiological and stress conditions. Dysfunction of autophagy has been causally associated with a variety of diseases, including tumorigenesis, diabetes and neurodegenerative disorders.

Previous work from Dr. ZHANG Hong’s lab revealed that worm epg-6, encoding a WD40 repeat-containing PtdIns(3)P binding protein, can regulates progression of omegasomes to autophagosomes.

Mammalian WDR45/WIPI4 is the ortholog of worm epg-6 and is essential for the basal autophagy pathway. Recent studies reveal that mutations in WDR45 cause beta-propeller protein-associated neurodegeneration (BPAN), which is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN patients display lower autophagic activity and accumulation of aberrant early autophagic structures, suggesting that WDR45 functions in maintaining neural homeostasis through its role in autophagy.

To reveal the relationship between WDR45 and neurodegeneration, Dr. ZHANG’s lab generated CNS-specific Wdr45 knockout mice (Nes-Wdr45^fl/Y mice), which displayed poor motor coordination, impaired learning and memory, and extensive axonal swelling. Wdr45 deficiency impaired the autophagic flux with accumulation of SQSTM1 and ubiquitin-positive aggregates in neurons and swollen axons. Nes-Wdr45^fl/Y mice recapitulate some hallmarks of BPAN, providing a model for revealing the disease pathogenesis of BPAN and also for understanding the neurodegeneration process underlying the pathogenesis of BPAN.

This study was published online in Autophagy entitled “The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis” by Dr. ZHANG Hong's lab at the Institute of Biophysics of Chinese Academy of Sciences.

This work was supported by the National Natural Science Foundation of China, grants from the National Basic Research Program of China to H.Z., and also a grant from the National Natural Science Foundation of China to Y.G.Z.. The research of Hong Zhang was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute. 

Figure: Nes-Wdr45^fl/Y mice exhibit learning and memory defect and axon swollen (Image by Dr. ZHANG Hong’s lab)