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


MeSH Major

  • Alleles
  • Carrier Proteins
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Membrane Glycoproteins
  • Niemann-Pick Disease, Type C


  • 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.

publication date

  • January 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4444535

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.4173-14.2015

PubMed ID

  • 26019327

Additional Document Info

start page

  • 8091

end page

  • 106


  • 35


  • 21