WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death

doi:10.1080/15548627.2019.1630224

CORC > 成都生物研究所 > 中国科学院成都生物研究所 > 国家天然药物工程技术研究中心 > 天然产物研究

	WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death
	Wan, Huida 4; Wang, Qi 4; Chen, Xiuting 4; Zeng, Qiufang 4; Shao, Yanjiao 4; Fang, Houqin 4; Liao, Xun 3; Li, Hu-Song 2; Liu, Ming-Gang 2; Xu, Tian-Le 2
刊名	AUTOPHAGY
	2020
卷号	16 期号:3 页码:531-547
关键词	ER stress neuronal apoptosis quantitative proteomics UPR WDR45
ISSN号	1554-8627
DOI	10.1080/15548627.2019.1630224
产权排序	2
文献子类	Article
英文摘要	Mutations in the macroautophagy/autophagy gene WDR45 cause beta-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.
学科主题	Biology
URL标识	查看原文
WOS关键词	PROTEIN-ASSOCIATED NEURODEGENERATION ; ENDOPLASMIC-RETICULUM TURNOVER ; TAUROURSODEOXYCHOLIC ACID ; STATIC ENCEPHALOPATHY ; MOUSE MODEL ; BILE-ACID ; AUTOPHAGY ; STRESS ; DISEASE ; MECHANISMS
WOS研究方向	Cell Biology
语种	英语
出版者	TAYLOR & FRANCIS INC
WOS记录号	WOS:000473098300001
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/31090]
专题	国家天然药物工程技术研究中心_天然产物研究
作者单位	1.Cent South Univ, Xiangya Med Sch, Xiangya Hosp, Inst Precis Med, Changsha, Hunan, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Physiol, Collaborat Innovat Ctr Brain Sci, Shanghai, Peoples R China; 3.Chinese Acad Sci, Chengdu Inst Biol, Chengdu, Sichuan, Peoples R China; 4.East China Normal Univ, Sch Life Sci, Shanghai Key Lab Regulatory Biol, Shanghai Key Lab Brain Funct Genom, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Wan, Huida,Wang, Qi,Chen, Xiuting,et al. WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death[J]. AUTOPHAGY,2020,16(3):531-547.
APA	Wan, Huida.,Wang, Qi.,Chen, Xiuting.,Zeng, Qiufang.,Shao, Yanjiao.,...&Liao, Lujian.(2020).WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death.AUTOPHAGY,16(3),531-547.
MLA	Wan, Huida,et al."WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death".AUTOPHAGY 16.3(2020):531-547.