气候变化领域集成服务门户(CCPortal): GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice

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DOI	10.1073/pnas.2022261118
	GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice
	Yuan W.; Lu L.; Rao M.; Huang Y.; Liu C.-E.; Liu S.; Zhao Y.; Liu H.; Zhu J.; Chao T.; Wu C.; Ren J.; Lv L.; Li W.; Qi S.; Liang Y.; Yue S.; Gao J.; Zhang Z.; Kong E.
发表日期	2021
ISSN	00278424
卷号	118 期号:13
英文摘要	The homeostasis of protein palmitoylation and depalmitoylation is essential for proper physiological functions in various tissues, in particular the central nervous system (CNS). The dysfunction of PPT1 (PPT1-KI, infantile neuronal ceroid lipofuscinosis [INCL] mouse model), which catalyze the depalmitoylation process, results in serious neurodegeneration accompanied by severe astrogliosis in the brain. Endeavoring to determine critical factors that might account for the pathogenesis in CNS by palm-proteomics, glial fibrillary acidic protein (GFAP) was spotted, indicating that GFAP is probably palmitoylated. Questions concerning if GFAP is indeed palmitoylated in vivo and how palmitoylation of GFAP might participate in neural pathology remain unexplored and are waiting to be investigated. Here we show that GFAP is readily palmitoylated in vitro and in vivo; specifically, cysteine-291 is the unique palmitoylated residue in GFAP. Interestingly, it was found that palmitoylated GFAP promotes astrocyte proliferation in vitro. Furthermore, we showed that PPT1 depalmitoylates GFAP, and the level of palmitoylated GFAP is overwhelmingly up-regulated in PPT1-knockin mice, which lead us to speculate that the elevated level of palmitoylated GFAP might accelerate astrocyte proliferation in vivo and ultimately led to astrogliosis in INCL. Indeed, blocking palmitoylation by mutating cysteine-291 into alanine in GFAP attenuate astrogliosis, and remarkably, the concurrent neurodegenerative pathology in PPT1-knockin mice. Together, these findings demonstrate that hyperpalmitoylated GFAP plays critical roles in regulating the pathogenesis of astrogliosis and neurodegeneration in the CNS, and most importantly, pinpointing that cysteine-291 in GFAP might be a valuable pharmaceutical target for treating INCL and other potential neurodegenerative diseases. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Astrogliosis; GFAP; Neurodegeneration; PPT1; Protein palmitoylation
语种	英语
scopus关键词	alanine; cysteine; cysteine 291; glial fibrillary acidic protein; palmitoyl protein thioesterase; PPT1 protein; unclassified drug; animal cell; animal experiment; animal tissue; Article; astrocyte; astrocytosis; cell function; cell proliferation; controlled study; degenerative disease; disease association; disease exacerbation; human; human cell; in vitro study; in vivo study; molecular pathology; mouse; nonhuman; palmitoylation; priority journal; protein degradation; protein function; protein protein interaction; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180075
作者单位	Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453000, China; Henan Key Laboratory of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, China; Department of Urology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, National Collaborative Innovation Center, Chengdu, 610041, China; School of Medicine, Nankai University, Tianjin, 300071, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221000, China
推荐引用方式 GB/T 7714	Yuan W.,Lu L.,Rao M.,et al. GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice[J],2021,118(13).
APA	Yuan W..,Lu L..,Rao M..,Huang Y..,Liu C.-E..,...&Kong E..(2021).GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.Proceedings of the National Academy of Sciences of the United States of America,118(13).
MLA	Yuan W.,et al."GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice".Proceedings of the National Academy of Sciences of the United States of America 118.13(2021).