The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis

Abstract

WDR45/WIPI4, encoding a WD40 repeat-containing PtdIns(3)P binding protein, is essential for the basal autophagy pathway. Mutations in WDR45 cause the neurodegenerative disease β-propeller protein-associated neurodegeneration (BPAN), a subtype of NBIA. We generated CNS-specific Wdr45 knockout mice, which exhibit poor motor coordination, greatly impaired learning and memory, and extensive axon swelling with numerous axon spheroids. Autophagic flux is defective and SQSTM1 (sequestosome-1)/p62 and ubiquitin-positive protein aggregates accumulate in neurons and swollen axons. Nes-Wdr45^fl/Y mice recapitulate some hallmarks of BPAN, including cognitive impairment and defective axonal homeostasis, providing a model for revealing the disease pathogenesis of BPAN and also for investigating the possible role of autophagy in axon maintenance.

Keywords:

• autophagy
• axon swelling
• learning and memory
• neurodegeneration
• Wdr45/Wipi4

Abbreviations:

• ACTB, β-actin
• AMC, aminomethylcoumarin
• Atg, autophagy-related
• BPAN, β-propeller protein-associated neurodegeneration
• CALB, calbindin
• CNS, central nervous system
• DCN, deep cerebellar nuclei
• Ei24, etoposide-induced gene 24
• epg, ectopic P granule
• fEPSP, field excitatory postsynaptic potential
• GFAP, glial fibrillary acid protein
• H&E, hematoxylin and eosin
• KO, knockout
• LC3, microtubule-associated protein 1 light chain 3
• LTP, long-term potentiation
• MBP, myelin basic protein
• NBIA, neurodegeneration with brain iron accumulation
• RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3
• rpm, rotations per min
• SENDA, static encephalopathy of childhood with neurodegeneration in adulthood
• SQSTM1, sequestosome-1
• WDR5/WIPI4, WD repeat domain 45
• WT, wild type.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful to the National Institute of Biological Sciences Transgenic Research Center for generating Wdr45 conditional KO mice, and Dr. Isabel Hanson for editing work. We also thank the animal facility at the Institute of Biophysics, Chinese Academy of Sciences for mice maintenance. Electron microscopy work was performed at the Center for Biological Imaging (http://cbi.ibp.ac.cn), Institute of Biophysics.

Funding

This work was supported by the National Natural Science Foundation of China (31421002, 31225018), grants from the National Basic Research Program of China (2013CB910100, 2011CB910100) to HZ, and also a grant from the National Natural Science Foundation of China (31401184) to YGZ. The research of Hong Zhang was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute.