Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Neurosurgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Nat Commun. 2024 Sep 6;15(1):7791. doi: 10.1038/s41467-024-52142-7.
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.
多发性硬化症（MS）是一种使人衰弱的脱髓鞘疾病，其特征是少突胶质细胞前体细胞（OPC）分化不足和星形胶质细胞异常增生导致的髓鞘再生失败。对临床标本的全面细胞图谱重新分析表明，CLU 在 MS 患者的活跃病变中表达升高，与特定星形胶质细胞亚型相关。我们的研究发现，患者组织的活跃病变以及雌性 MS 小鼠模型中星形胶质细胞 CLU 水平升高。CLU 给药刺激原代星形胶质细胞增殖，同时阻碍星形胶质细胞对髓鞘碎片的清除。有趣的是，CLU 过载直接抑制 OPC 分化并诱导 OPC 和 OL 凋亡。在机制上，CLU 通过极低密度脂蛋白受体抑制原代 OPC 中的 PI3K-AKT 信号。AKT 的药理学激活可挽救过量 CLU 对 OPC 造成的损伤，并改善胼胝体脱髓鞘。此外，CLU 的条件敲除成为一种有前途的干预措施，在 MS 小鼠模型中显示出改善的髓鞘再生过程和降低的严重程度。
