# A mouse model Niemann-Pick type C disease to test proteostasis therapies

> **NIH NIH R03** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $148,533

## Abstract

Niemann-Pick disease type C is an invariably fatal autosomal recessive lipid storage disease.
Patients develop a clinically heterogeneous phenotype that includes progressive
neurodegeneration and early death. Disease is commonly caused by loss-of-function mutations
in the NPC1 gene (95% of cases), encoding a multipass transmembrane glycoprotein required
for exporting unesterified cholesterol from late endosomes and lysosomes. The most common
disease-causing mutation (~20% of cases) is an isoleucine to threonine substitution at position
1061 (I1061T). I1061T NPC1 misfolds in the endoplasmic reticulum (ER) and is rapidly degraded
by the proteasome and ER-autophagy. Importantly, transient over-expression of I1061T in vitro
or treatment of I1061T NPC1 patient fibroblasts with ryanodine receptor antagonists drives
trafficking of mutant NPC1 to the lysosome where it is still functional. These observations have
spurred interest in developing proteostasis modulators to treat disease. These efforts have relied
on gene targeted mice in which the I1061T mutation was inserted into the mouse Npc1 gene to
test therapeutic strategies. However, our preliminary data indicate that there are marked
differences in how the human and mouse I1061T NPC1 proteins are handled by the cellular
quality control machinery. These previously unappreciated differences underscore the critical
need to develop a new model system that reliably reproduces human I1061T NPC1 proteostasis.
The rationale for this project is that developing humanized I1061T NPC1 mice will enable in vivo
testing of proteostatic therapeutics for Niemann-Pick C. To attain the overall objective of this
application, we will use genetic and biochemical approaches to pursue the following specific aim:
Develop and characterize humanized I1061T NPC1 mice. We expect that targeting the mouse
Npc1 gene to express human I1061T NPC1 protein will generate a robust model of disease, in
which misfolding and trafficking of the mutant NPC1 protein closely mimics the behavior of human
I1061T NPC1 as occurs in Niemann-Pick C patients.

## Key facts

- **NIH application ID:** 10038058
- **Project number:** 1R03NS117806-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANDREW P LIEBERMAN
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,533
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10038058

## Citation

> US National Institutes of Health, RePORTER application 10038058, A mouse model Niemann-Pick type C disease to test proteostasis therapies (1R03NS117806-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10038058. Licensed CC0.

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