Deciphering microglial activation in lysosomal storage diseases could leads the way to new therapeutic interventions Cougnoux, A.1, Drummond, R. A.2, Collar, A. L.2, Iben, J.R.3, Salman, A.1, Westgarth, H.1, Wassif, C. A.1,Cawley, N.X.1, Farhat, N.Y.1, Ozato, K.5, Lionakis, M. S.2 and Porter, F. D.1 1Division of Translational Medicine, EuniceKennedyShriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; 2Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; 3Molecular Genomics Core, EuniceKennedyShriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; 5Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative disorder with limited treatment options. It is associated with neuroinflammation; however, attempts to therapeutically target this aspect of the pathological cascade which contributes to neuronal loss has had mixed success. Thus, we applied flow cytometry, transcriptomic, metabolic and immunofluorescence techniques to functionally characterize microglial activation in NPC1. The microglial activation pattern was compared to other neurodegenerative and lysosomal storage diseases, using either published datasets or data generated as part of this project. This comparison demonstrates both unique and common features that may be amendable to therapeutic intervention. Treatment with 2-hydroxypropyl-β-cyclodextrin (VTS-270), a drug currently being studied for the treatment of NPC1 in a phase 3 clinical trial, reversed all microglia-associated defects in Npc1-/- animals. In addition, impairing microglia mediated neuroinflammation by genetic deletion of IRF8 in Npc1 mutant mice led to delayed symptoms and increased lifespan in addition to reducing microglial activation. In our characterization we measured an increase in CD22 expression, subsequently decreased by VTS-270 treatment in mouse and human. Collectively, these data provide the first in-depth analysis of microglia function in lysosomal storage disease and suggests possible new therapeutic approaches.
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