PT  - JOURNAL ARTICLE
AU  - Praggastis, Maria
AU  - Tortelli, Brett
AU  - Zhang, Jessie
AU  - Fujiwara, Hideji
AU  - Sidhu, Rohini
AU  - Chacko, Anita
AU  - Chen, Zhouji
AU  - Chung, Chan
AU  - Lieberman, Andrew P.
AU  - Sikora, Jakub
AU  - Davidson, Cristin
AU  - Walkley, Steven U.
AU  - Pipalia, Nina H.
AU  - Maxfield, Frederick R.
AU  - Schaffer, Jean E.
AU  - Ory, Daniel S.
TI  - A Murine Niemann-Pick C1 I1061T Knock-In Model Recapitulates the Pathological Features of the Most Prevalent Human Disease Allele
AID  - 10.1523/JNEUROSCI.4173-14.2015
DP  - 2015 May 27
TA  - The Journal of Neuroscience
PG  - 8091--8106
VI  - 35
IP  - 21
4099  - http://www.jneurosci.org/content/35/21/8091.short
4100  - http://www.jneurosci.org/content/35/21/8091.full
SO  - J. Neurosci.2015 May 27; 35
AB  - 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.