Journal
AUTOPHAGY
Volume 11, Issue 6, Pages 881-890Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1047127
Keywords
autophagy; axon swelling; learning and memory; neurodegeneration; Wdr45/Wipi4
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Funding
- National Natural Science Foundation of China [31421002, 31225018, 31401184]
- National Basic Research Program of China [2013CB910100, 2011CB910100]
- International Early Career Scientist grant from the Howard Hughes Medical Institute
- Grants-in-Aid for Scientific Research [25111005] Funding Source: KAKEN
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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 -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.
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