title: Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.
abstract: Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention.
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cougnoux
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cluzeau
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: I
authors.initials: I
authors.lastname: Williams
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: K
authors.initials: K
authors.lastname: Burkert
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
authors.forename: F D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009336:Necrosis; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C119724:AGFG1 protein, human; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D028861:Nuclear Pore Complex Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C490620:Ralbp1 protein, mouse; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse