Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation
Shiqian Han,
Qijun Wang,
Yongfeng Song,
Mao Pang,
Chunguang Ren,
Jing Wang,
Dongwei Guan,
Wei Xu,
Fangyong Li,
Fengchao Wang,
Xinyuan Zhou,
Carlos Fernández-Hernando,
Huiwen Zhang,
Dianqing Wu,
Zhijia Ye
Affiliations
Shiqian Han
Department of Tropical Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
Qijun Wang
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA; Departments of Pharmacology, Yale University School of Medicine, New Haven, CT06520, USA; Shanghai Institute of Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Yongfeng Song
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA; Departments of Pharmacology, Yale University School of Medicine, New Haven, CT06520, USA
Mao Pang
Laboratory Animal Research Center, Chongqing University School of Medicine, Chongqing 400044, China
Chunguang Ren
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA; Departments of Pharmacology, Yale University School of Medicine, New Haven, CT06520, USA
Jing Wang
Department of Tropical Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
Dongwei Guan
Laboratory Animal Research Center, Chongqing University School of Medicine, Chongqing 400044, China
Wei Xu
Biostatistics, Yale University School of Medicine, New Haven, CT 06520, USA
Fangyong Li
Biostatistics, Yale University School of Medicine, New Haven, CT 06520, USA
Fengchao Wang
Institute of Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China
Xinyuan Zhou
Department of Immunology, Third Military Medical University (Army Medical University), Chongqing 400038, China
Carlos Fernández-Hernando
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA; Comparative Medicine and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA
Huiwen Zhang
Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Dianqing Wu
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA; Departments of Pharmacology, Yale University School of Medicine, New Haven, CT06520, USA; Corresponding author
Zhijia Ye
Laboratory Animal Research Center, Chongqing University School of Medicine, Chongqing 400044, China; Corresponding author
Summary: 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 in 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 explanation for lithium’s effects on Npc1 mice. Thus, this study reveals a potential therapeutic option for NP-C patients as well as a strategy to reduce active STING/SREBP2 pathway.
