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- Title
The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C.
- Authors
Pluvinage, John V.; Sun, Jerry; Claes, Christel; Flynn, Ryan A.; Haney, Michael S.; Iram, Tal; Meng, Xiangling; Lindemann, Rachel; Riley, Nicholas M.; Danhash, Emma; Chadarevian, Jean Paul; Tapp, Emma; Gate, David; Kondapavulur, Sravani; Cobos, Inma; Chetty, Sundari; Pașca, Anca M.; Pașca, Sergiu P.; Berry-Kravis, Elizabeth; Bertozzi, Carolyn R.
- Abstract
Human-specific interaction: Niemann-Pick type C disease (NPC) is a lysosomal storage disorder caused by autosomal recessive mutations in NPC1 or NPC2. Previous data showed that CD22 is increased in the brain of patients with NPC. Now, Pluvinage et al. studied the role of CD22 in NPC pathophysiology and showed that, whereas CD22 is expressed in microglia in mice, oligodendrocytes seem to be the major source of CD22 in the human brain. Blocking the interaction of CD22 with its partner on microglia, IGF2R, reduced lysosome dysfunction in patient-derived microglia-like cells. The CD22-IGF2R interaction represents a potential therapeutic target for treating NPC-mediated cellular abnormalities. 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.
- Subjects
MICROGLIA; SOMATOMEDIN A; INSULIN-like growth factor receptors; MYELOID cells; LYSOSOMAL storage diseases; IMMUNOGLOBULINS; CEREBROSPINAL fluid; FAMILIAL spastic paraplegia
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 622, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abg2919