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J Neurosci. 2015 May 27;35(21):8091-106. doi: 10.1523/JNEUROSCI.4173-14.2015.

A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele.

Author information

1
Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
2
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109.
3
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.
4
Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065.
5
Diabetic Cardiovascular Disease Center and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, dory@wustl.edu.

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.

KEYWORDS:

NPC1; Niemann-Pick C; cholesterol; lysosomal storage; neurodegeneration; protein misfolding

PMID:
26019327
PMCID:
PMC4444535
DOI:
10.1523/JNEUROSCI.4173-14.2015
[Indexed for MEDLINE]
Free PMC Article

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