Article Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation

作者全名："Han, Shiqian; Wang, Qijun; Song, Yongfeng; Pang, Mao; Ren, Chunguang; Wang, Jing; Guan, Dongwei; Xu, Wei; Li, Fangyong; Wang, Fengchao; Zhou, Xinyuan; Fernandez-Hernando, Carlos; Zhang, Huiwen; Wu, Dianqing; Ye, Zhijia"

作者地址："[Han, Shiqian; Wang, Jing] Army Med Univ, Third Mil Med Univ, Dept Trop Med, Chongqing 400038, Peoples R China; [Wang, Qijun; Song, Yongfeng; Ren, Chunguang; Fernandez-Hernando, Carlos; Wu, Dianqing] Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA; [Wang, Qijun; Song, Yongfeng; Ren, Chunguang; Wu, Dianqing] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA; [Wang, Qijun] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Shanghai Inst Immunol, Shanghai 200092, Peoples R China; [Pang, Mao; Guan, Dongwei; Ye, Zhijia] Chongqing Univ, Sch Med, Lab Anim Res Ctr, Chongqing 400044, Peoples R China; [Xu, Wei; Li, Fangyong] Yale Univ, Sch Med, Biostat, New Haven, CT 06520 USA; [Wang, Fengchao] Army Med Univ, Third Mil Med Univ, Inst Combined Injury, Chongqing 400038, Peoples R China; [Zhou, Xinyuan] Third Mil Med Univ, Army Med Univ, Dept Immunol, Chongqing 400038, Peoples R China; [Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Comparat Med & Pathol, New Haven, CT 06520 USA; [Fernandez-Hernando, Carlos] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Pediat Endocrinol & Genet, Shanghai 200092, Peoples R China; [Han, Shiqian] Army Med Univ, Frontier Med Training Brigade Mil Med Univ, Chongqing 831200, Xinjiang, Peoples R China"

通信作者："Wu, DQ (通讯作者)，Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA.; Wu, DQ (通讯作者)，Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA.; Ye, ZJ (通讯作者)，Chongqing Univ, Sch Med, Lab Anim Res Ctr, Chongqing 400044, Peoples R China."

来源：ISCIENCE

ESI学科分类：　

WOS号：WOS:001000266500001

JCR分区：Q1

影响因子：4.6

年份：2023

卷号：26

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder associated with progressive neurodegenerative phenotypes. Its therapeutic options are very limited. Here, we show that lithium treatment improves ataxia and feeding phenotypes, attenuates cerebellar inflammation and degeneration, and extends survival in Npc1 mouse models. In addition, lithium suppresses STING activation, SREBP2 processing to its mature form and the expression of the target genes the Npc1 mice and in Npc1-deficient fibroblasts. Lithium impedes STING/SREBP2 transport from the ER to the Golgi, a step required for STING activation and SREBP2 processing, probably by lowering cytosolic calcium concentrations. This effect of lithium on STING/SREBP2 transport provides a mechanistic explana-tion for lithium's effects on Npc1 mice. Thus, this study reveals a potential thera-peutic option for NP-C patients as well as a strategy to reduce active STING/ SREBP2 pathway."

基金机构："National Natural Science Foundation (NNSF) of China [31371393, 81170471, 31870021]; Science and Technology Innovation Project of Army Medical University [2022XQN09]; National Institute of Health [1R35HL135805]"

基金资助正文："ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation (NNSF) of China (31371393, 81170471, 31870021) , the Science and Technology Innovation Project of Army Medical University (2022XQN09) and the National Institute of Health grant 1R35HL135805. The graphical abstract was created with BioRender.com ."