A murine Niemann-Pick C1 (NPC1) I1061T knockin model recapitulates the pathological features of the most prevalent human disease allele

Praggastis M, Tortelli B, Zhang J, Fujiwara H, Sidhu R, Chacko A, Chen Z, Lieberman AP, Davidson C, Walkley SU, Pipalia NH, Maxfield FR, Schaffer JE, and Ory DS: 2015 J Neuroscience, 35:8091-8106. PMCID: PMC4444535 Read More

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.

Full Text

.

Posted on October 20, 2016
Posted in: HPAN, Lysosome, Neurodegeneration, Publications Authors: