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The most prevalent mutation, NPC1<jats:sup>I1061T<\/jats:sup>, 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<jats:italic>in vivo<\/jats:italic>because of lack of a suitable animal model. Whereas the prominent features of human NPC1 disease are replicated in the null<jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>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<jats:italic>Npc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse, this<jats:italic>Npc1<jats:sup>tm(I1061T)Dso<\/jats:sup><\/jats:italic>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<jats:sup>I1061T<\/jats:sup>protein has a reduced half-life<jats:italic>in vivo<\/jats:italic>, 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.<\/jats:p>","DOI":"10.1523\/jneurosci.4173-14.2015","type":"journal-article","created":{"date-parts":[[2015,5,27]],"date-time":"2015-05-27T18:18:15Z","timestamp":1432750695000},"page":"8091-8106","source":"Crossref","is-referenced-by-count":123,"title":["A Murine Niemann-Pick C1 I1061T Knock-In Model Recapitulates the Pathological Features of the Most Prevalent Human Disease 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