2. Academic Validation
  3. Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation

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

  • iScience. 2023 Apr 8;26(5):106613. doi: 10.1016/j.isci.2023.106613.
Shiqian Han 1,  Qijun Wang 2 3 4,  Yongfeng Song 2 3,  Mao Pang 5,  Chunguang Ren 2 3,  Jing Wang 1,  Dongwei Guan 5,  Wei Xu 6,  Fangyong Li 6,  Fengchao Wang 7,  Xinyuan Zhou 8,  Carlos Fernández-Hernando 2 9,  Huiwen Zhang 10,  Dianqing Wu 2 3,  Zhijia Ye 5
Affiliations

Affiliations

  • 1 Department of Tropical Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 2 Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT06520, USA.
  • 3 Departments of Pharmacology, Yale University School of Medicine, New Haven, CT06520, USA.
  • 4 Shanghai Institute of Immunology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
  • 5 Laboratory Animal Research Center, Chongqing University School of Medicine, Chongqing 400044, China.
  • 6 Biostatistics, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 7 Institute of Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 8 Department of Immunology, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 9 Comparative Medicine and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 10 Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
PMID: 37128603 DOI: 10.1016/j.isci.2023.106613
Abstract

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.

Keywords

Cell biology; Developmental neuroscience; Treatment.

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