2. Academic Validation
  3. Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases

Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases

  • Nat Commun. 2024 Sep 6;15(1):7791. doi: 10.1038/s41467-024-52142-7.
Chen Chen # 1 2,  Yaqing Shu # 1,  Chengkai Yan # 1,  Huilu Li 1,  Zhenchao Huang 2,  ShiShi Shen 1,  Chunxin Liu 3,  Yanjun Jiang 4 5 6,  Shixiong Huang 7,  Zhanhang Wang 8,  Feng Mei 9,  Feng Qin 10,  Xiaodong Liu 11 12 13,  Wei Qiu 14
Affiliations

Affiliations

  • 1 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5 Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 7 Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, China.
  • 8 Department of Neurology, 999 Brain Hospital, Guangzhou, China.
  • 9 Department of Histology and Embryology, Third Military Medical University (Army Medical University), Chongqing, China.
  • 10 Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. qinfeng2@mail.sysu.edu.cn.
  • 11 Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
  • 12 Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
  • 13 Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. xdliu@cuhk.edu.hk.
  • 14 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. qiuwei@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39242637 DOI: 10.1038/s41467-024-52142-7
Abstract

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs Apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of Akt rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.

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