2. Academic Validation
  3. Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation

Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation

  • Cell Death Dis. 2024 May 21;15(5):350. doi: 10.1038/s41419-024-06737-z.
Wenli Cui # 1 2,  Jing Yang # 1 2,  Chuanyun Tu 1 2,  Ziting Zhang 1 2,  Huifang Zhao 1,  Yan Qiao 3,  Yanqiu Li 3,  Wulin Yang 4,  Kah-Leong Lim 5,  Quanhong Ma 6,  Chengwu Zhang 7 8,  Li Lu 9 10
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
  • 2 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
  • 3 Analytical Instrumentation Center & State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, 030001, Shanxi, China.
  • 4 Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
  • 5 Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Singapore.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China. maquanhong@suda.edu.cn.
  • 7 School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. chengwu_zhang@sxmu.edu.cn.
  • 8 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. chengwu_zhang@sxmu.edu.cn.
  • 9 School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. luli@sxmu.edu.cn.
  • 10 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. luli@sxmu.edu.cn.
  • # Contributed equally.
PMID: 38773070 DOI: 10.1038/s41419-024-06737-z
Abstract

Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.

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