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- Title
A Murine Niemann-Pick C1 I1061T Knock-In Model Recapitulates the Pathological Features of the Most Prevalent Human Disease Allele.
- Authors
Praggastis, Maria; Tortelli, Brett; Zhang, Jessie; Fujiwara, Hideji; Sidhu, Rohini; Chacko, Anita; Zhouji Chen; Chan Chung; Lieberman, Andrew P.; Sikora, Jakub; Davidson, Cristin; Walkley, Steven U.; Pipalia, Nina H.; Maxfield, Frederick R.; Schaffer, Jean E.; Ory, Daniel S.
- 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, NPC1I1061T, 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 Npc1tm(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 NPC1I1061T 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.
- Subjects
NIEMANN-Pick diseases; DISEASE prevalence; ALLELES; LYSOSOMAL storage diseases; GENETIC code; LABORATORY mice
- Publication
Journal of Neuroscience, 2015, Vol 35, Issue 21, p8091
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4173-14.2015