The autophagy geneWdr45/Wipi4regulates learning and memory function and axonal homeostasis

Abstract

(2015) The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis, Autophagy, 11:6, 881-890, DOI: 10.1080/15548627.2015 Abbreviations: ACTB, b-actin; AMC, aminomethylcoumarin; Atg, autophagy-related; BPAN, b-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.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 b-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.

Mechanisms of neuronal homeostasis: Autophagy in the axon

“…Future studies will elucidate precisely how autophagy is regulated and tuned to the compartment-specific needs of the neuron to facilitate normal neuronal function, and how these processes are altered in response to various modalities of stress. Recent evidence implicates autophagy proteins in learning and memory (Zhao et al, 2015), but the mechanisms underlying these phenotypes are largely unknown. Another key outstanding question is whether the autophagic pathway is exploited to deliver critical signals from the distal axon to the soma to perhaps relay information concerning the integrity of the axonal compartment.…”

Eaten alive: novel insights into autophagy from multicellular model systems

“…Mice deficient in Ei24, Epg5 , and Wipi4 (the mammalian Epg6 homolog) have also been generated. Ablation of these autophagy genes in neurons results in the accumulation of ubiqui-tin-positive protein aggregates, p62 aggregates, and elevated levels of LC3, indicating that autophagic flux is impaired [35–37]. Recent human genetic studies have revealed that recessive EPG5 mutations are causally related to the multisystem disorder Vici syndrome [38], while de novo mutations in WIPI4 , the homolog of C. elegans epg-6 [33], cause a subtype of neurodegeneration with brain iron accumulation called β-propeller-protein-associated neurodegeneration; also known as static encephalopathy of childhood with neurodegeneration in adulthood [39,40].…”

Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury

“…In the nervous system, autophagosomes have been observed in cultured neurons or in vivo (30)(31)(32)(33)(34)(35). Inhibition of autophagy by genetic elimination of autophagy-determination proteins has been shown to cause neuronal degeneration in mouse cerebellum Purkinje cells or other neurons in various brain regions (36,37). By contrast, pharmacological inhibition of autophagy attenuates acute degeneration of retinal ganglion cell (RGC) axons (38,39).…”