WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death | |
Wan, Huida4; Wang, Qi4; Chen, Xiuting4; Zeng, Qiufang4; Shao, Yanjiao4; Fang, Houqin4; Liao, Xun3; Li, Hu-Song2; Liu, Ming-Gang2; Xu, Tian-Le2 | |
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. |
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