Journal article
Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease
JCI insight, Vol.7(23), e160308
12/06/2022
DOI: 10.1172/jci.insight.160308
PMCID: PMC9746915
PMID: 36301667
Abstract
The folding and trafficking of transmembrane glycoproteins are essential for cellular homeostasis and are compromised in many diseases. In Niemann-Pick type C disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, the transmembrane glycoprotein NPC1 misfolds due to disease-causing missense mutations. While mutant NPC1 has emerged as a robust target for proteostasis modulators, drug development efforts have been unsuccessful in mouse models. Here, we demonstrated unexpected differences in trafficking through the medial Golgi between mouse and human I1061T-NPC1, a common disease-causing mutant. We established that these distinctions are governed by differences in the NPC1 protein sequence rather than by variations in the endoplasmic reticulum-folding environment. Moreover, we demonstrated direct effects of mutant protein trafficking on the response to small molecules that modulate the endoplasmic reticulum-folding environment by affecting Ca++ concentration. Finally, we developed a panel of isogenic human NPC1 iNeurons expressing WT, I1061T-, and R934L-NPC1 and demonstrated their utility in testing these candidate therapeutics. Our findings identify important rules governing mutant NPC1's response to proteostatic modulators and highlight the importance of species-and mutation-specific responses for therapy development.
Details
- Title: Subtitle
- Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease
- Creators
- Mark L. Schultz - University of MichiganKylie J. Schache - University of MichiganRuth D. Azaria - University of MichiganEsmee Q. Kuiper - University of MichiganSteven Erwood - Hosp Sick Children Res Inst, Program Genet & Genome Biol, Toronto, ON, CanadaEvgueni A. Ivakine - Hosp Sick Children Res Inst, Program Genet & Genome Biol, Toronto, ON, CanadaNicole Y. Farhat - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentForbes D. Porter - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentKoralege C. Pathmasiri - Univ Illinois, Dept Chem, Chicago, IL USAStephanie M. Cologna - Univ Illinois, Dept Chem, Chicago, IL USAMichael D. Uhler - University of MichiganAndrew P. Lieberman - University of Michigan
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.7(23), e160308
- DOI
- 10.1172/jci.insight.160308
- PMID
- 36301667
- PMCID
- PMC9746915
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 18
- Grant note
- Ara Parseghian Medical Research Foundation Support for Accelerated Research for Niemann-Pick Type C NIH Clinical Center Bench ZIA HD008989 / Eunice Kennedy Shriver National Institutes of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Hope for Marian Niemann-Pick Canada Andrew Coppola Foundation R01 NS063967; R01 NS122746; K01 DK124450; R01NS114413 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA University of Pennsylvania Orphan Disease Center in partnership Charles Woodson Collaborative Research Award
- Language
- English
- Date published
- 12/06/2022
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9984366276402771
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