title: Immune dysfunction in Niemann-Pick disease type C.
abstract: Lysosomal storage diseases are inherited monogenic disorders in which lysosome function is compromised. Although individually very rare, they occur at a collective frequency of approximately one in five thousand live births and usually have catastrophic consequences for health. The lysosomal storage diseases Niemann-Pick disease type C (NPC) is caused by mutations predominantly in the lysosomal integral membrane protein NPC1 and clinically presents as a progressive neurodegenerative disorder. In this article we review data that demonstrate significant dysregulation of innate immunity in NPC, which occurs both in peripheral organs and the CNS. In particular pro-inflammatory responses promote disease progression and anti-inflammatory drugs provide benefit in animal models of the disease and are an attractive target for clinical intervention in this disorder. Niemann-Pick disease type C is a rare, devastating, inherited lysosomal storage disease with a unique cellular phenotype characterized by lysosomal accumulation of sphingosine, various glycosphingolipids and cholesterol and a reduction in lysosomal calcium. In this review we highlight the impact of the disease on innate immune activities in both the central nervous system (CNS) and peripheral tissues and discuss their contributions to pathology and the underlying mechanisms.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Platt
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Annelise O
authors.initials: AO
authors.lastname: Speak
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Colaco
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Gray
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Williams
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Kerri-Lee
authors.initials: KL
authors.lastname: Wallom
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D000818:Animals; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis* / Q000276:immunology*
keywords: Niemann Pick type C; cytokine; inflammation; lysosomal storage disease; lysosome; microglia; neurodegeneration