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

• Published in: The Journal of neuroscience Vol. 35; no. 21; pp. 8091 - 8106
• Main Authors: Praggastis, Maria, Tortelli, Brett, Zhang, Jessie, Fujiwara, Hideji, Sidhu, Rohini, Chacko, Anita, Chen, Zhouji, Chung, Chan, Lieberman, Andrew P, Sikora, Jakub, Davidson, Cristin, Walkley, Steven U, Pipalia, Nina H, Maxfield, Frederick R, Schaffer, Jean E, Ory, Daniel S
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 27-05-2015
• Subjects: Alleles; Animals; Carrier Proteins - genetics; Cells, Cultured; Disease Models, Animal; Female; Gene Knock-In Techniques - methods; Humans; Male; Membrane Glycoproteins - genetics; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Disease, Type C - pathology; Prevalence; neurodegeneration; cholesterol; NPC1; Niemann-Pick C; protein misfolding; lysosomal storage
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.4173-14.2015

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.