title: 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.
authors.affiliation: a State Key Laboratory of Biomacromolecules; Institute of Biophysics; Chinese Academy of Sciences ; Beijing , China.
authors.forename: Yan G
authors.initials: YG
authors.lastname: Zhao
authors.forename: Le
authors.initials: L
authors.lastname: Sun
authors.forename: Guangyan
authors.initials: G
authors.lastname: Miao
authors.forename: Cuicui
authors.initials: C
authors.lastname: Ji
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Huayu
authors.initials: H
authors.lastname: Sun
authors.forename: Lin
authors.initials: L
authors.lastname: Miao
authors.forename: Saori R
authors.initials: SR
authors.lastname: Yoshii
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D001369:Axons / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D007858:Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C000606909:Wdr45 protein, mouse
keywords: 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; 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; SENDA, static encephalopathy of childhood with neurodegeneration in adulthood; SQSTM1, sequestosome-1; WDR5/WIPI4, WD repeat domain 45; WT, wild type.; Wdr45/Wipi4; autophagy; axon swelling; epg, ectopic P granule; fEPSP, field excitatory postsynaptic potential; learning and memory; neurodegeneration; rpm, rotations per min