Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target

A Cougnoux; C Cluzeau; S Mitra; R Li; I Williams; K Burkert; X Xu; C A Wassif; W Zheng; F D Porter

doi:10.1038/cddis.2016.16

Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target

Cell Death Dis. 2016 Mar 17;7(3):e2147. doi: 10.1038/cddis.2016.16.

Authors

A Cougnoux¹, C Cluzeau¹, S Mitra², R Li³, I Williams¹, K Burkert¹, X Xu³, C A Wassif¹, W Zheng³, F D Porter¹

Affiliations

¹ 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.
² Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
³ National Center for Advancing Translational Sciences, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.

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.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line
GTPase-Activating Proteins / genetics
GTPase-Activating Proteins / metabolism
Humans
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Mice
Mice, Mutant Strains
Necrosis
Neural Stem Cells / metabolism*
Neural Stem Cells / pathology
Niemann-Pick C1 Protein
Niemann-Pick Disease, Type C / genetics
Niemann-Pick Disease, Type C / metabolism*
Niemann-Pick Disease, Type C / pathology
Niemann-Pick Disease, Type C / therapy*
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / metabolism
Proteins / genetics
Proteins / metabolism
Purkinje Cells / metabolism*
Purkinje Cells / pathology
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism

Substances

AGFG1 protein, human
Carrier Proteins
GTPase-Activating Proteins
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
NPC1 protein, human
Niemann-Pick C1 Protein
Npc1 protein, mouse
Nuclear Pore Complex Proteins
Proteins
RNA-Binding Proteins
Ralbp1 protein, mouse
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse

Grants and funding

Intramural NIH HHS/United States