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

Chen Chen, Yaqing Shu, Chengkai Yan, Huilu Li, Zhenchao Huang, ShiShi Shen, Chunxin Liu, Yanjun Jiang, Shixiong Huang, Zhanhang Wang, Feng Mei, Feng Qin (), Xiaodong Liu () and Wei Qiu ()
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Chen Chen: The Third Affiliated Hospital of Sun Yat-sen University
Yaqing Shu: The Third Affiliated Hospital of Sun Yat-sen University
Chengkai Yan: The Third Affiliated Hospital of Sun Yat-sen University
Huilu Li: The Third Affiliated Hospital of Sun Yat-sen University
Zhenchao Huang: The Third Affiliated Hospital of Sun Yat-sen University
ShiShi Shen: The Third Affiliated Hospital of Sun Yat-sen University
Chunxin Liu: The Third Affiliated Hospital of Sun Yat-sen University
Yanjun Jiang: The Chinese University of Hong Kong
Shixiong Huang: Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University)
Zhanhang Wang: 999 Brain Hospital
Feng Mei: Third Military Medical University (Army Medical University)
Feng Qin: The Third Affiliated Hospital of Sun Yat-sen University
Xiaodong Liu: The Chinese University of Hong Kong
Wei Qiu: The Third Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52142-7

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