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Research Article
LYSOSOMAL STORAGE DISEASES

The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C

Science Translational Medicine
1 Dec 2021
Vol 13, Issue 622

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.

Abstract

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.

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REFERENCES AND NOTES

1
C. de Duve, B. C. Pressman, R. Gianetto, R. Wattiaux, F. Appelmans, Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 60, 604–617 (1955).
2
F. M. Platt, A. d’Azzo, B. L. Davidson, E. F. Neufeld, C. J. Tifft, Lysosomal storage diseases. Nat. Rev. Dis. Primers. 4, 27 (2018).
3
A. Ballabio, J. S. Bonifacino, Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).
4
J. Aharon-Peretz, H. Rosenbaum, R. Gershoni-Baruch, Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).
5
J. V. Reddy, I. G. Ganley, S. R. Pfeffer, Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling. PLOS ONE 1, e19 (2006).
6
S. M. Cologna, X.-S. Jiang, P. S. Backlund, C. V. M. Cluzeau, M. K. Dail, N. M. Yanjanin, S. Siebel, C. L. Toth, H.-S. Jun, C. A. Wassif, A. L. Yergey, F. D. Porter, Quantitative proteomic analysis of Niemann-Pick disease, type C1 cerebellum identifies protein biomarkers and provides pathological insight. PLOS ONE 7, e47845 (2012).
7
M. Malnar, S. Hecimovic, N. Mattsson, H. Zetterberg, Bidirectional links between Alzheimer’s disease and Niemann-Pick type C disease. Neurobiol. Dis. 72(Pt. A), 37–47 (2014).
8
L.-W. Jin, F.-S. Shie, I. Maezawa, I. Vincent, T. Bird, Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am. J. Pathol. 164, 975–985 (2004).
9
S. Torres, C. M. García-Ruiz, J. C. Fernandez-Checa, Mitochondrial Cholesterol in Alzheimer’s disease and Niemann-Pick type C disease. Front. Neurol. 10, 1168 (2019).
10
M. Walterfang, M. Fahey, P. Desmond, A. Wood, M. L. Seal, C. Steward, C. Adamson, C. Kokkinos, M. Fietz, D. Velakoulis, White and gray matter alterations in adults with Niemann-Pick disease type C: A cross-sectional study. Neurology 75, 49–56 (2010).
11
S. E. Bianconi, D. I. Hammond, N. Y. Farhat, A. Dang Do, K. Jenkins, A. Cougnoux, K. Martin, F. D. Porter, Evaluation of age of death in Niemann-Pick disease, type C: Utility of disease support group websites to understand natural history. Mol. Genet. Metab. 126, 466–469 (2019).
12
A. Cougnoux, R. A. Drummond, A. L. Collar, J. R. Iben, A. Salman, H. Westgarth, C. A. Wassif, N. X. Cawley, N. Y. Farhat, K. Ozato, M. S. Lionakis, F. D. Porter, Microglia activation in Niemann–Pick disease, type C1 is amendable to therapeutic intervention. Hum. Mol. Genet. 27, 2076–2089 (2018).
13
L. Kavetsky, K. K. Green, B. R. Boyle, F. A. K. Yousufzai, Z. M. Padron, S. E. Melli, V. L. Kuhnel, H. M. Jackson, R. E. Blanco, G. R. Howell, I. Soto, Increased interactions and engulfment of dendrites by microglia precede Purkinje cell degeneration in a mouse model of Niemann Pick Type-C. Sci. Rep. 9, 14722 (2019).
14
E. Gabandé-Rodríguez, A. Pérez-Cañamás, B. Soto-Huelin, D. N. Mitroi, S. Sánchez-Redondo, E. Martínez-Sáez, C. Venero, H. Peinado, M. D. Ledesma, Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders. EMBO J. 38, e99553 (2019).
15
A. Colombo, L. Dinkel, S. A. Müller, L. Sebastian Monasor, M. Schifferer, L. Cantuti-Castelvetri, J. König, L. Vidatic, T. Bremova-Ertl, A. P. Lieberman, S. Hecimovic, M. Simons, S. F. Lichtenthaler, M. Strupp, S. A. Schneider, S. Tahirovic, Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nat. Commun. 12, 1158 (2021).
16
M. Baudry, Y. Yao, D. Simmons, J. Liu, X. Bi, Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: Immunohistochemical observations of microglia and astroglia. Exp. Neurol. 184, 887–903 (2003).
17
S. M. Cologna, C. V. M. Cluzeau, N. M. Yanjanin, P. S. Blank, M. K. Dail, S. Siebel, C. L. Toth, C. A. Wassif, A. P. Lieberman, F. D. Porter, Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. J. Inherit. Metab. Dis. 37, 83–92 (2014).
18
J. V. Pluvinage, M. S. Haney, B. A. H. Smith, J. Sun, T. Iram, L. Bonanno, L. Li, D. P. Lee, D. W. Morgens, A. C. Yang, S. R. Shuken, D. Gate, M. Scott, P. Khatri, J. Luo, C. R. Bertozzi, M. C. Bassik, T. Wyss-Coray, CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187–192 (2019).
19
R. D. Hodge, T. E. Bakken, J. A. Miller, K. A. Smith, E. R. Barkan, L. T. Graybuck, J. L. Close, B. Long, N. Johansen, O. Penn, Z. Yao, J. Eggermont, T. Höllt, B. P. Levi, S. I. Shehata, B. Aevermann, A. Beller, D. Bertagnolli, K. Brouner, T. Casper, C. Cobbs, R. Dalley, N. Dee, S.-L. Ding, R. G. Ellenbogen, O. Fong, E. Garren, J. Goldy, R. P. Gwinn, D. Hirschstein, C. D. Keene, M. Keshk, A. L. Ko, K. Lathia, A. Mahfouz, Z. Maltzer, M. McGraw, T. N. Nguyen, J. Nyhus, J. G. Ojemann, A. Oldre, S. Parry, S. Reynolds, C. Rimorin, N. V. Shapovalova, S. Somasundaram, A. Szafer, E. R. Thomsen, M. Tieu, G. Quon, R. H. Scheuermann, R. Yuste, S. M. Sunkin, B. Lelieveldt, D. Feng, L. Ng, A. Bernard, M. Hawrylycz, J. W. Phillips, B. Tasic, H. Zeng, A. R. Jones, C. Koch, E. S. Lein, Conserved cell types with divergent features in human versus mouse cortex. Nature, 61–68 (2019).
20
L. Geirsdottir, E. David, H. Keren-Shaul, A. Weiner, S. C. Bohlen, J. Neuber, A. Balic, A. Giladi, F. Sheban, C.-A. Dutertre, C. Pfeifle, F. Peri, A. Raffo-Romero, J. Vizioli, K. Matiasek, C. Scheiwe, S. Meckel, K. Mätz-Rensing, F. van der Meer, F. R. Thormodsson, C. Stadelmann, N. Zilkha, T. Kimchi, F. Ginhoux, I. Ulitsky, D. Erny, I. Amit, M. Prinz, Cross-species single-cell analysis reveals divergence of the primate microglia program. Cell 179, 1609–1622.e16 (2019).
21
E. Khrameeva, I. Kurochkin, D. Han, P. Guijarro, S. Kanton, M. Santel, Z. Qian, S. Rong, P. Mazin, M. Sabirov, M. Bulat, O. Efimova, A. Tkachev, S. Guo, C. C. Sherwood, J. G. Camp, S. Pääbo, B. Treutlein, P. Khaitovich, Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains. Genome Res. 30, 776–789 (2020).
22
Y.-N. Jiang, X. Cai, H.-M. Zhou, W.-D. Jin, M. Zhang, Y. Zhang, X.-X. Du, Z.-H. K. Chen, Diagnostic and prognostic roles of soluble CD22 in patients with Gram-negative bacterial sepsis. Hepatobiliary Pancreat. Dis. Int. 14, 523–529 (2015).
23
K. Matsushita, I. Margulies, M. Onda, S. Nagata, M. Stetler-Stevenson, R. J. Kreitman, Soluble CD22 as a tumor marker for hairy cell leukemia. Blood 112, 2272–2277 (2008).
24
L. D. Powell, D. Sgroi, E. R. Sjoberg, I. Stamenkovic, A. Varki, Natural ligands of the B cell adhesion molecule CD22 beta carry N-linked oligosaccharides with alpha-2,6-linked sialic acids that are required for recognition. J. Biol. Chem. 268, 7019–7027 (1993).
25
J. Ereño-Orbea, T. Sicard, H. Cui, M. T. Mazhab-Jafari, S. Benlekbir, A. Guarné, J. L. Rubinstein, J.-P. Julien, Molecular basis of human CD22 function and therapeutic targeting. Nat. Commun. 8, 746 (2017).
26
M. S. Haney, C. J. Bohlen, D. W. Morgens, J. A. Ousey, A. A. Barkal, C. K. Tsui, B. K. Ego, R. Levin, R. A. Kamber, H. Collins, A. Tucker, A. Li, D. Vorselen, L. Labitigan, E. Crane, E. Boyle, L. Jiang, J. Chan, E. Rincon, W. J. Greenleaf, B. Li, M. P. Snyder, I. L. Weissman, J. A. Theriot, S. R. Collins, B. A. Barres, M. C. Bassik, Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. Nat. Genet. 50, 1716–1727 (2018).
27
D. W. Morgens, R. M. Deans, A. Li, M. C. Bassik, Systematic comparison of CRISPR/Cas9 and RNAi screens for essential genes. Nat. Biotechnol. 34, 634–636 (2016).
28
T. Hennet, D. Chui, J. C. Paulson, J. D. Marth, Immune regulation by the ST6Gal sialyltransferase. Proc. Natl. Acad. Sci. U.S.A. 95, 4504–4509 (1998).
29
T. N. C. Ramya, E. Weerapana, L. Liao, Y. Zeng, H. Tateno, L. Liao, J. R. Yates 3rd, B. F. Cravatt, J. C. Paulson, In situ trans ligands of CD22 identified by glycan-protein photocross-linking-enabled proteomics. Mol. Cell. Proteomics 9, 1339–1351 (2010).
30
L. D. Powell, R. K. Jain, K. L. Matta, S. Sabesan, A. Varki, Characterization of sialyloligosaccharide binding by recombinant soluble and native cell-associated CD22. Evidence for a minimal structural recognition motif and the potential importance of multisite binding. J. Biol. Chem. 270, 7523–7532 (1995).
31
S. Kornfeld, Structure and function of the mannose 6-phosphate/insulin like growth factor II receptors. Annu. Rev. Biochem. 61, 307–330 (1992).
32
J. C. Fratantoni, C. W. Hall, E. F. Neufeld, Hurler and Hunter syndromes: Mutual correction of the defect in cultured fibroblasts. Science 162, 570–572 (1968).
33
G. D. Vladutiu, M. C. Rattazzi, Excretion-reuptake route of beta-hexosaminidase in normal and I-cell disease cultured fibroblasts. J. Clin. Invest. 63, 595–601 (1979).
34
E. F. Neufeld, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, G. Sunder-Plassmann, Eds. (Oxford PharmaGenesis, 2011).
35
S. M. Banik, K. Pedram, S. Wisnovsky, G. Ahn, N. M. Riley, C. R. Bertozzi, Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020).
36
A. Amritraj, K. Peake, A. Kodam, C. Salio, A. Merighi, J. E. Vance, S. Kar, Increased activity and altered subcellular distribution of lysosomal enzymes determine neuronal vulnerability in Niemann-Pick type C1-deficient mice. Am. J. Pathol. 175, 2540–2556 (2009).
37
C. V. M. Cluzeau, D. E. Watkins-Chow, R. Fu, B. Borate, N. Yanjanin, M. K. Dail, C. D. Davidson, S. U. Walkley, D. S. Ory, C. A. Wassif, W. J. Pavan, F. D. Porter, Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1. Hum. Mol. Genet. 21, 3632–3646 (2012).
38
S. Kim, J. Ock, A. K. Kim, H. W. Lee, J.-Y. Cho, D. R. Kim, J.-Y. Park, K. Suk, Neurotoxicity of microglial cathepsin D revealed by secretome analysis. J. Neurochem. 103, 2640–2650 (2007).
39
A. M. Cataldo, R. A. Nixon, Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl. Acad. Sci. U.S.A. 87, 3861–3865 (1990).
40
A. Amritraj, Y. Wang, T. J. Revett, D. Vergote, D. Westaway, S. Kar, Role of cathepsin D in U18666A-induced neuronal cell death: Potential implication in Niemann-Pick type C disease pathogenesis. J. Biol. Chem. 288, 3136–3152 (2013).
41
D. E. Sleat, J. A. Wiseman, M. El-Banna, S. M. Price, L. Verot, M. M. Shen, G. S. Tint, M. T. Vanier, S. U. Walkley, P. Lobel, Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc. Natl. Acad. Sci. U.S.A. 101, 5886–5891 (2004).
42
M. B. L. Winkler, R. T. Kidmose, M. Szomek, K. Thaysen, S. Rawson, S. P. Muench, D. Wüstner, B. P. Pedersen, Structural insight into eukaryotic sterol transport through niemann-pick type C proteins. Cell 179, 485–497.e18 (2019).
43
H. Qian, X. Wu, X. Du, X. Yao, X. Zhao, J. Lee, H. Yang, N. Yan, Structural basis of Low-pH-Dependent lysosomal cholesterol egress by NPC1 and NPC2. Cell 182, 98–111.e18 (2020).
44
D. E. Sleat, A. Tannous, I. Sohar, J. A. Wiseman, H. Zheng, M. Qian, C. Zhao, W. Xin, R. Barone, K. B. Sims, D. F. Moore, P. Lobel, Proteomic Analysis of brain and cerebrospinal fluid from the three major forms of neuronal ceroid lipofuscinosis reveals potential biomarkers. J. Proteome Res. 16, 3787–3804 (2017).
45
M. Willenborg, C. K. Schmidt, P. Braun, J. Landgrebe, K. von Figura, P. Saftig, E.-L. Eskelinen, Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation. J. Lipid Res. 46, 2559–2569 (2005).
46
G. Griffiths, B. Hoflack, K. Simons, I. Mellman, S. Kornfeld, The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 52, 329–341 (1988).
47
S. Waguri, F. Dewitte, R. Le Borgne, Y. Rouillé, Y. Uchiyama, J.-F. Dubremetz, B. Hoflack, Visualization of TGN to endosome trafficking through fluorescently labeled MPR and AP-1 in living cells. Mol. Biol. Cell 14, 142–155 (2003).
48
N. M. Dahms, P. Lobel, S. Kornfeld, Mannose 6-phosphate receptors and lysosomal enzyme targeting. J. Biol. Chem. 264, 12115–12118 (1989).
49
S. X. Lin, W. G. Mallet, A. Y. Huang, F. R. Maxfield, Endocytosed cation-independent mannose 6-phosphate receptor traffics via the endocytic recycling compartment en route to the trans-Golgi network and a subpopulation of late endosomes. Mol. Biol. Cell 15, 721–733 (2004).
50
H. Weintraub, A. Abramovici, U. Sandbank, A. D. Booth, P. G. Pentchev, B. Sela, Dysmyelination in NCTR-Balb/C mouse mutant with a lysosomal storage disorder. Morphological survey. Acta Neuropathol. 74, 374–381 (1987).
51
B. Samra, E. Jabbour, F. Ravandi, H. Kantarjian, N. J. Short, Evolving therapy of adult acute lymphoblastic leukemia: State-of-the-art treatment and future directions. J. Hematol. Oncol. 13, 70 (2020).
52
S. J. Meyer, A. T. Linder, C. Brandl, L. Nitschke, B cell siglecs-news on signaling and its interplay with ligand binding. Front. Immunol. 9, 2820 (2018).
53
M. Praggastis, B. Tortelli, J. Zhang, H. Fujiwara, R. Sidhu, A. Chacko, Z. Chen, C. Chung, A. P. Lieberman, J. Sikora, C. Davidson, S. U. Walkley, N. H. Pipalia, F. R. Maxfield, J. E. Schaffer, D. S. Ory, A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J. Neurosci. 35, 8091–8106 (2015).
54
E. M. Abud, R. N. Ramirez, E. S. Martinez, L. M. Healy, C. H. H. Nguyen, S. A. Newman, A. V. Yeromin, V. M. Scarfone, S. E. Marsh, C. Fimbres, C. A. Caraway, G. M. Fote, A. M. Madany, A. Agrawal, R. Kayed, K. H. Gylys, M. D. Cahalan, B. J. Cummings, J. P. Antel, A. Mortazavi, M. J. Carson, W. W. Poon, M. Blurton-Jones, iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).
55
A. McQuade, M. Coburn, C. H. Tu, J. Hasselmann, H. Davtyan, M. Blurton-Jones, Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Mol. Neurodegener. 13, 67 (2018).
56
J. Hasselmann, M. A. Coburn, W. England, D. X. Figueroa Velez, S. Kiani Shabestari, C. H. Tu, A. McQuade, M. Kolahdouzan, K. Echeverria, C. Claes, T. Nakayama, R. Azevedo, N. G. Coufal, C. Z. Han, B. J. Cummings, H. Davtyan, C. K. Glass, L. M. Healy, S. P. Gandhi, R. C. Spitale, M. Blurton-Jones, Development of a chimeric model to study and manipulate human microglia in vivo. Neuron 103, 1016–1033.e10 (2019).
57
M. E. Gelsthorpe, N. Baumann, E. Millard, S. E. Gale, S. J. Langmade, J. E. Schaffer, D. S. Ory, Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. J. Biol. Chem. 283, 8229–8236 (2008).
58
F. Lu, Q. Liang, L. Abi-Mosleh, A. Das, J. K. De Brabander, J. L. Goldstein, M. S. Brown, Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection. eLife 4, e12177 (2015).
59
S. Safaiyan, N. Kannaiyan, N. Snaidero, S. Brioschi, K. Biber, S. Yona, A. L. Edinger, S. Jung, M. J. Rossner, M. Simons, Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016).
60
H. Mathys, J. Davila-Velderrain, Z. Peng, F. Gao, S. Mohammadi, J. Z. Young, M. Menon, L. He, F. Abdurrob, X. Jiang, A. J. Martorell, R. M. Ransohoff, B. P. Hafler, D. A. Bennett, M. Kellis, L.-H. Tsai, Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019).
61
Y. Zhou, W. M. Song, P. S. Andhey, A. Swain, T. Levy, K. R. Miller, P. L. Poliani, M. Cominelli, S. Grover, S. Gilfillan, M. Cella, T. K. Ulland, K. Zaitsev, A. Miyashita, T. Ikeuchi, M. Sainouchi, A. Kakita, D. A. Bennett, J. A. Schneider, M. R. Nichols, S. A. Beausoleil, J. D. Ulrich, D. M. Holtzman, M. N. Artyomov, M. Colonna, Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020).
62
M. Olah, V. Menon, N. Habib, M. F. Taga, Y. Ma, C. J. Yung, M. Cimpean, A. Khairallah, G. Coronas-Samano, R. Sankowski, D. Grün, A. A. Kroshilina, D. Dionne, R. A. Sarkis, G. R. Cosgrove, J. Helgager, J. A. Golden, P. B. Pennell, M. Prinz, J. P. G. Vonsattel, A. F. Teich, J. A. Schneider, D. A. Bennett, A. Regev, W. Elyaman, E. M. Bradshaw, P. L. De Jager, Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease. Nat. Commun. 11, 6129 (2020).
63
A. Cougnoux, R. A. Drummond, M. Fellmeth, F. Navid, A. L. Collar, J. Iben, A. B. Kulkarni, J. Pickel, R. Schiffmann, C. A. Wassif, N. X. Cawley, M. S. Lionakis, F. D. Porter, Unique molecular signature in mucolipidosis type IV microglia. J. Neuroinflammation 16, 276 (2019).
64
P. Douvaras, V. Fossati, Generation and isolation of oligodendrocyte progenitor cells from human pluripotent stem cells. Nat. Protoc. 10, 1143–1154 (2015).
65
P. Peschl, K. Schanda, B. Zeka, K. Given, D. Böhm, K. Ruprecht, A. Saiz, A. Lutterotti, K. Rostásy, R. Höftberger, T. Berger, W. Macklin, H. Lassmann, M. Bradl, J. L. Bennett, M. Reindl, Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J. Neuroinflammation 14, 208 (2017).
66
E. Gerrits, Y. Heng, E. W. G. M. Boddeke, B. J. L. Eggen, Transcriptional profiling of microglia; current state of the art and future perspectives. Glia 68, 740–755 (2020).
67
N. Thrupp, C. Sala Frigerio, L. Wolfs, N. G. Skene, N. Fattorelli, S. Poovathingal, Y. Fourne, P. M. Matthews, T. Theys, R. Mancuso, B. de Strooper, M. Fiers, Single-nucleus RNA-Seq is not suitable for detection of microglial activation genes in humans. Cell Rep. 32, 108189 (2020).
68
J. D. Welch, V. Kozareva, A. Ferreira, C. Vanderburg, C. Martin, E. Z. Macosko, Single-cell multi-omic integration compares and contrasts features of brain cell identity. Cell 177, 1873–1887.e17 (2019).
69
S. Heybrock, K. Kanerva, Y. Meng, C. Ing, A. Liang, Z.-J. Xiong, X. Weng, Y. Ah Kim, R. Collins, W. Trimble, R. Pomès, G. G. Privé, W. Annaert, M. Schwake, J. Heeren, R. Lüllmann-Rauch, S. Grinstein, E. Ikonen, P. Saftig, D. Neculai, Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export. Nat. Commun. 10, 3521 (2019).
70
A. Singhal, L. Szente, J. E. K. Hildreth, B. Song, Hydroxypropyl-beta and -gamma cyclodextrins rescue cholesterol accumulation in Niemann–Pick C1 mutant cell via lysosome-associated membrane protein 1. Cell Death Dis. 9, 1019 (2018).
71
J. Li, S. R. Pfeffer, Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export. eLife 5, e21635 (2016).
72
Y.-C. Twu, T.-S. Lee, Y.-L. Lin, S.-M. Hsu, Y.-H. Wang, C.-Y. Liao, C.-K. Wang, Y.-C. Liang, Y.-J. Liao, Niemann-Pick Type C2 protein mediates hepatic stellate cells activation by regulating free cholesterol accumulation. Int. J. Mol. Sci. 17, 1122 (2016).
73
P. T. Massa, S. Saha, C. Wu, K. W. Jarosinski, Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes. Glia 29, 376–385 (2000).
74
T. Kodachi, S. Matsumoto, M. Mizuguchi, H. Osaka, N. Kanai, E. Nanba, K. Ohno, T. Yamagata, Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C. Neuropathology 37, 426–430 (2017).
75
S. Takikita, T. Fukuda, I. Mohri, T. Yagi, K. Suzuki, Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J. Neuropathol. Exp. Neurol. 63, 660–673 (2004).
76
T. A. Ray, K. Cochran, C. Kozlowski, J. Wang, G. Alexander, M. A. Cady, W. J. Spencer, P. A. Ruzycki, B. S. Clark, A. Laeremans, M.-X. He, X. Wang, E. Park, Y. Hao, A. Iannaccone, G. Hu, O. Fedrigo, N. P. Skiba, V. Y. Arshavsky, J. N. Kay, Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease. Nat. Commun. 11, 3328 (2020).
77
K. Strauss, C. Goebel, H. Runz, W. Möbius, S. Weiss, I. Feussner, M. Simons, A. Schneider, Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J. Biol. Chem. 285, 26279–26288 (2010).
78
M. Hane, D. Y. Chen, A. Varki, Human-specific microglial Siglec-11 transcript variant has the potential to affect polysialic acid-mediated brain functions at a distance. Glycobiology 31, 231–242 (2021).
79
D. J. Miller, T. Duka, C. D. Stimpson, S. J. Schapiro, W. B. Baze, M. J. McArthur, A. J. Fobbs, A. M. M. Sousa, N. Sestan, D. E. Wildman, L. Lipovich, C. W. Kuzawa, P. R. Hof, C. C. Sherwood, Prolonged myelination in human neocortical evolution. Proc. Natl. Acad. Sci. U.S.A. 109, 16480–16485 (2012).
80
C. H. Vite, W. Ding, C. Bryan, P. O’Donnell, K. Cullen, D. Aleman, M. E. Haskins, T. Van Winkle, Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease. Pediatr. Res. 64, 544–549 (2008).
81
C. D. Davidson, A. L. Gibson, T. Gu, L. L. Baxter, B. E. Deverman, K. Beadle, A. A. Incao, J. L. Rodriguez-Gil, H. Fujiwara, X. Jiang, R. J. Chandler, D. S. Ory, V. Gradinaru, C. P. Venditti, W. J. Pavan, Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice. Life Sci Alliance 4, e202101040 (2021).
82
M. C. Patterson, W. S. Garver, R. Giugliani, J. Imrie, H. Jahnova, F. J. Meaney, Y. Nadjar, M. T. Vanier, P. Moneuse, O. Morand, D. Rosenberg, B. Schwierin, B. Héron, Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study. J. Inherit. Metab. Dis. 43, 1060–1069 (2020).
83
T. Kirkegaard, J. Gray, D. A. Priestman, K.-L. Wallom, J. Atkins, O. D. Olsen, A. Klein, S. Drndarski, N. H. T. Petersen, L. Ingemann, D. A. Smith, L. Morris, C. Bornæs, S. H. Jørgensen, I. Williams, A. Hinsby, C. Arenz, D. Begley, M. Jäättelä, F. M. Platt, Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci. Transl. Med. 8, 355ra118 (2016).
84
M. S. Alam, M. Getz, K. Haldar, Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model. Sci. Transl. Med. 8, 326ra23 (2016).
85
E. Kaya, D. A. Smith, C. Smith, L. Morris, T. Bremova-Ertl, M. Cortina-Borja, P. Fineran, K. J. Morten, J. Poulton, B. Boland, J. Spencer, M. Strupp, F. M. Platt, Acetyl-Leucine slows disease progression in lysosomal storage disorders. bioRxiv 2020.05.20.105973 (2020).
86
D. S. Ory, E. A. Ottinger, N. Y. Farhat, K. A. King, X. Jiang, L. Weissfeld, E. Berry-Kravis, C. D. Davidson, S. Bianconi, L. A. Keener, R. Rao, A. Soldatos, R. Sidhu, K. A. Walters, X. Xu, A. Thurm, B. Solomon, W. J. Pavan, B. N. Machielse, M. Kao, S. A. Silber, J. C. McKew, C. C. Brewer, C. H. Vite, S. U. Walkley, C. P. Austin, F. D. Porter, Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: A non-randomised, open-label, phase 1-2 trial. Lancet 390, 1758–1768 (2017).
87
M. P. Hughes, D. A. Smith, L. Morris, C. Fletcher, A. Colaco, M. Huebecker, J. Tordo, N. Palomar, G. Massaro, E. Henckaerts, S. N. Waddington, F. M. Platt, A. A. Rahim, AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann–Pick type C1 disease. Hum. Mol. Genet. 27, 3079–3098 (2018).
88
M. E. Maes, G. Colombo, R. Schulz, S. Siegert, Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges. Neurosci. Lett. 707, 134310 (2019).
89
Y. Zhang, S. A. Sloan, L. E. Clarke, C. Caneda, C. A. Plaza, P. D. Blumenthal, H. Vogel, G. K. Steinberg, M. S. B. Edwards, G. Li, J. A. Duncan III, S. H. Cheshier, L. M. Shuer, E. F. Chang, G. A. Grant, M. G. H. Gephart, B. A. Barres, Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
90
K. H. Loh, P. S. Stawski, A. S. Draycott, N. D. Udeshi, E. K. Lehrman, D. K. Wilton, T. Svinkina, T. J. Deerinck, M. H. Ellisman, B. Stevens, S. A. Carr, A. Y. Ting, Proteomic analysis of unbounded cellular compartments: Synaptic clefts. Cell 166, 1295–1307.e21 (2016).
91
V. Hung, N. D. Udeshi, S. S. Lam, K. H. Loh, K. J. Cox, K. Pedram, S. A. Carr, A. Y. Ting, Spatially resolved proteomic mapping in living cells with the engineered peroxidase APEX2. Nat. Protoc. 11, 456–475 (2016).
92
J. Cox, M. Mann, MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
93
S. Tyanova, T. Temu, P. Sinitcyn, A. Carlson, M. Y. Hein, T. Geiger, M. Mann, J. Cox, The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).

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Published In

Science Translational Medicine
Volume 13 | Issue 622
December 2021

Submission history

Received: 22 December 2020
Accepted: 8 October 2021

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Acknowledgments

We thank the patients and their families for donating tissue samples used for this research and J. Cottrell at the NIH NeuroBioBank at the University of Maryland for collecting tissue samples. We thank the members of the Wyss-Coray, Blurton-Jones, and Bertozzi laboratories for feedback and support; S. Pfeffer, M. Abu-Remaileh, and U. Medoh for critical reading of the manuscript; T. Branon and S. Han for helpful discussions; H. Zhang and K. Dickey for laboratory management; B. Lehallier for RNA-seq analysis scripts; M. Macauley for reagents; L. Kean for helpful discussions; and B. Carter for flow cytometry technical expertise. Schematics were created with BioRender.com.
Funding: This work was funded by the Department of Veterans Affairs (T.W.-C.), the National Institute on Aging (RF1-AG064897-02 to T.W.-C., F30AG060638 to J.V.P., and T32AG000266 to M.S.H.), the UCI-ADRC (NIA P30 AG066519 to M.B.-J.), the National Institute of General Medical Sciences (R01-GM058867 to C.R.B. and K00CA212454 to N.M.R.), the NOMIS Foundation (T.W.-C.), the Glenn Foundation for Aging Research (T.W.-C.), the NYSCF Robertson Stem Cell Investigator Award (S.P.P.), the Stanford Wu Tsai Neurosciences Big Idea Project on Human Brain Organogenesis (S.P.P.), the Zuckerberg Initiative Ben Barres Investigator Award (S.P.P.) and the Wu Tsai Neurosciences Institute (T.W.-C. and C.R.B.).
Author contributions: J.V.P. and T.W.-C. conceptualized the study. J.V.P. wrote the manuscript, and all authors edited the manuscript. J.V.P. and J.S. designed, performed, or analyzed all experiments. R.A.F. and N.M.R. designed, performed, and analyzed LC-MS experiments. M.S.H. and R.L. designed, performed, and analyzed CRISPR screening experiments. C.C., E.D., and J.P.C. performed iMGL experiments. T.I., X.M., and S.C. performed or supervised oligodendrocyte culture experiments. E.T., D.G., and I.C. performed or supervised histology experiments. S.K. performed computational analyses. A.M.P. collected and processed human primary cortical tissues. E.B.-K. collected and provided CSF samples. T.W.-C., M.B.-J., C.R.B., and S.P.P. supervised the work.
Competing interests: C.R.B. is a cofounder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, InterVenn Bio, and Redwood Bioscience (a subsidiary of Catalent) and a member of the Board of Directors of Eli Lilly and Company. M.B.-J. is a cofounder of NovoGlia Inc. and coinventor of patent application WO/2018/160496, related to the differentiation of stem cells into microglia. T.W.-C., J.V.P., M.S.H., and C.R.B. are coinventors on a patent application related to the work in this paper (US16/956,339, “Compositions and methods for treating age related disesases”). T.W.-C. and J.V.P. are coinventors on a patent application related to the work in this paper (PCT/US21/32875, “Compositions and methods for treating lysosomal storage disorders”).
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Raw sequencing data are available on NCBI GEO (accession number GSE184243).

Authors

Affiliations

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Present address: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Christel Claes
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
Roles: Investigation, Methodology, Validation, Visualization, and Writing - original draft.
Stem Cell Program, Children’s Hospital Boston, Boston, MA 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Roles: Investigation, Methodology, Resources, and Validation.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Conceptualization, Formal analysis, Investigation, and Software.
Tal Iram
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Role: Investigation.
Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Conceptualization, Investigation, Resources, and Validation.
Rachel Lindemann
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Formal analysis, Investigation, Resources, and Validation.
Department of Chemistry and ChEM-H, Stanford University, Stanford, CA 94305, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94304, USA.
Roles: Formal analysis, Investigation, Methodology, Validation, and Writing - review & editing.
Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Roles: Formal analysis, Investigation, and Writing - original draft.
Jean Paul Chadarevian
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Roles: Conceptualization, Methodology, and Validation.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Role: Investigation.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, and Validation.
Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Roles: Formal analysis, Software, and Writing - review & editing.
Inma Cobos
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Resources, Validation, Writing - original draft, and Writing - review & editing.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Roles: Investigation, Methodology, Project administration, Resources, Supervision, and Validation.
Division of Neonatology, Department of Pediatrics, Stanford University, Stanford, CA 94304, USA.
Roles: Investigation, Resources, and Writing - review & editing.
Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Roles: Methodology and Resources.
Rush University Medical Center, Chicago, IL 60612, USA.
Roles: Resources and Writing - review & editing.
Department of Chemistry and ChEM-H, Stanford University, Stanford, CA 94305, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94304, USA.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, and Writing - review & editing.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA.
Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA.
Wu Tsai Neurosciences Institute, Stanford, CA, 94305, USA.
Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, and Writing - review & editing.

Funding Information

The Alzheimer’s Disease Research Center at the University of California, Irvine: P30AG066519
Alzheimer’s Disease Research Center: NIA P50 AG16573
Stanford University Training Program on Aging: T32AG000266

Notes

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Corresponding author. Email: [email protected]

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