Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC). However, the role of CD22 in the human brain remains unknown. In contrast to previous findings in mice, here, we show that CD22 is expressed by oligodendrocytes in the human brain and binds to sialic acid–dependent ligands on microglia. Using unbiased genetic and proteomic screens, we identify insulin-like growth factor 2 receptor (IGF2R) as the binding partner of sCD22 on human myeloid cells. Targeted truncation of IGF2R revealed that sCD22 docks near critical mannose 6-phosphate–binding domains, where it disrupts lysosomal protein trafficking. Interfering with the sCD22-IGF2R interaction using CD22 blocking antibodies ameliorated lysosome dysfunction in human NPC1 mutant induced pluripotent stem cell–derived microglia-like cells without harming oligodendrocytes in vitro. These findings reinforce the differences between mouse and human microglia and provide a candidate microglia-directed immunotherapeutic to treat NPC.

中文翻译：

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CD22-IGF2R 相互作用是 Niemann-Pick C 型小胶质细胞溶酶体功能障碍的治疗靶点

溶酶体功能障碍是罕见的溶酶体贮积病和常见的与年龄相关的神经退行性疾病的共同特征。小胶质细胞是大脑中的巨噬细胞，由于清除垂死神经元、髓磷脂和碎片的吞噬压力，特别容易受到溶酶体功能障碍的影响。CD22 是衰老小鼠大脑中小胶质细胞稳态的负调节因子，尼曼-匹克 C 型疾病 (NPC) 患者的脑脊液中可溶性 CD22 (sCD22) 增加。然而，CD22 在人脑中的作用仍不清楚。与之前在小鼠中的发现相反，我们在这里发现 CD22 由人脑中的少突胶质细胞表达，并与小胶质细胞上的唾液酸依赖性配体结合。使用公正的遗传和蛋白质组学筛选，我们确定胰岛素样生长因子 2 受体 (IGF2R) 是人类骨髓细胞上 sCD22 的结合伴侣。IGF2R 的靶向截断表明 sCD22 停靠在关键的 6-磷酸甘露糖结合域附近，从而破坏溶酶体蛋白质运输。使用 CD22 阻断抗体干扰 sCD22-IGF2R 相互作用，可改善人NPC1突变体诱导的多能干细胞衍生的小胶质细胞样细胞的溶酶体功能障碍，且在体外不会损害少突胶质细胞。这些发现强化了小鼠和人类小胶质细胞之间的差异，并提供了一种候选的小胶质细胞定向免疫疗法来治疗鼻咽癌。