Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
Commun Biol. 2024 Oct 22;7(1):1373. doi: 10.1038/s42003-024-07057-w.
Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.
CLN3 功能丧失突变导致少年型巴滕病，其特征是神经退行性变和早期神经炎症。目前尚不清楚 CLN3 功能丧失如何导致早期神经炎症。在这里，我们全面研究了 Cln3 小鼠的小胶质细胞，这是一种遗传上准确的疾病模型。小胶质细胞中 CLN3 功能的丧失导致溶酶体储存物质的积累和亚细胞细胞器的异常形态。此外，病理蛋白质组学特征表明溶酶体功能缺陷和异常脂质代谢。与这些发现一致，CLN3 缺陷型小胶质细胞无法有效地清除髓鞘并代谢相关脂质，表现出脂滴形成和胆固醇积累缺陷。因此，我们还观察到衰老的 Cln3 小鼠大脑中的髓鞘完整性受损。自噬诱导剂和降低胆固醇的药物纠正了观察到的小胶质细胞表型。综上所述，这些数据表明 CLN3 缺陷型小胶质细胞存在细胞自主性缺陷，影响其支持神经元细胞健康的能力，表明针对小胶质细胞的靶向治疗方法应考虑用于 CLN3 疾病。
