title: A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele.
abstract: Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol-sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1(I1061T), encodes a misfolded protein with a reduced half-life caused by ER-associated degradation. Therapies directed at stabilization of the mutant NPC1 protein reduce cholesterol storage in fibroblasts but have not been tested in vivo because of lack of a suitable animal model. Whereas the prominent features of human NPC1 disease are replicated in the null Npc1(-/-) mouse, this model is not amenable to examining proteostatic therapies. The objective of the present study was to develop an NPC1 I1061T knock-in mouse in which to test proteostatic therapies. Compared with the Npc1(-/-) mouse, this Npc1(tm(I1061T)Dso) model displays a less severe, delayed form of NPC1 disease with respect to weight loss, decreased motor coordination, Purkinje cell death, lipid storage, and premature death. The murine NPC1(I1061T) protein has a reduced half-life in vivo, consistent with protein misfolding and rapid ER-associated degradation, and can be stabilized by histone deacetylase inhibition. This novel mouse model faithfully recapitulates human NPC1 disease and provides a powerful tool for preclinical evaluation of therapies targeting NPC1 protein variants with compromised stability.
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Maria
authors.initials: M
authors.lastname: Praggastis
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Brett
authors.initials: B
authors.lastname: Tortelli
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jessie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Anita
authors.initials: A
authors.lastname: Chacko
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Chan
authors.identifier: http://orcid.org/0000-0003-0510-8996
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Cristin
authors.initials: C
authors.lastname: Davidson
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Nina H
authors.initials: NH
authors.lastname: Pipalia
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.affiliation: Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, dory@wustl.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
mesh_terms: D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000473:pathology*; D015995:Prevalence
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein
keywords: NPC1; Niemann-Pick C; cholesterol; lysosomal storage; neurodegeneration; protein misfolding