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

Maria Praggastis, Brett Tortelli, Jessie Zhang, Hideji Fujiwara, Rohini Sidhu, Anita Chacko, Zhouji Chen, Chan Chung, Andrew P. Lieberman, Jakub Sikora, Cristin Davidson, Steven U. Walkley, Nina H. Pipalia, Frederick R. Maxfield, Jean E. Schaffer, Daniel S. Ory

Research output: Contribution to journalArticle

37 Scopus citations


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 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 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.

Original languageEnglish (US)
Pages (from-to)8091-8106
Number of pages16
JournalJournal of Neuroscience
Issue number21
Publication statusPublished - May 27 2015



  • Cholesterol
  • Lysosomal storage
  • NPC1
  • Neurodegeneration
  • Niemann-Pick C
  • Protein misfolding

ASJC Scopus subject areas

  • Neuroscience(all)

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