TY - JOUR
T1 - A murine Niemann-Pick C1 I1061T knock-In model recapitulates the pathological features of the most prevalent human disease allele
AU - Praggastis, Maria
AU - Tortelli, Brett
AU - Zhang, Jessie
AU - Fujiwara, Hideji
AU - Sidhu, Rohini
AU - Chacko, Anita
AU - Chen, Zhouji
AU - Chung, Chan
AU - Lieberman, Andrew P.
AU - Sikora, Jakub
AU - Davidson, Cristin
AU - Walkley, Steven U.
AU - Pipalia, Nina H.
AU - Maxfield, Frederick R.
AU - Schaffer, Jean E.
AU - Ory, Daniel S.
N1 - Publisher Copyright:
© 2015 the authors.
PY - 2015/5/27
Y1 - 2015/5/27
N2 - 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.
AB - 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.
KW - Cholesterol
KW - Lysosomal storage
KW - NPC1
KW - Neurodegeneration
KW - Niemann-Pick C
KW - Protein misfolding
UR - http://www.scopus.com/inward/record.url?scp=84930260924&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4173-14.2015
DO - 10.1523/JNEUROSCI.4173-14.2015
M3 - Article
C2 - 26019327
AN - SCOPUS:84930260924
SN - 0270-6474
VL - 35
SP - 8091
EP - 8106
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 21
ER -