Journal article
Mutant induced neurons and humanized mice enable identification of Niemann-Pick C1 proteostatic therapies
JCI insight, Vol.9(20), e179525
10/22/2024
DOI: 10.1172/jci.insight.179525
PMCID: PMC11530122
PMID: 39207850
Abstract
Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step towards the development of disease-modifying therapies.Therapeutics that rescue folding, trafficking, and function of disease-causing missense mutants are sought for a host of human diseases, but efforts to leverage model systems to test emerging strategies have met with limited success. Such is the case for Niemann-Pick type C1 disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, progressive neurodegeneration, and early death. NPC1, a multipass transmembrane glycoprotein, is synthesized in the endoplasmic reticulum and traffics to late endosomes/lysosomes, but this process is often disrupted in disease. We sought to identify small molecules that promote folding and enable lysosomal localization and functional recovery of mutant NPC1. We leveraged a panel of isogenic human induced neurons expressing distinct NPC1 missense mutations. We used this panel to rescreen compounds that were reported previously to correct NPC1 folding and trafficking. We established mo56-hydroxycholesterol (mo56Hc) as a potent pharmacological chaperone for several NPC1 mutants. Furthermore, we generated mice expressing human I1061T NPC1, a common mutation in patients. We demonstrated that this model exhibited disease phenotypes and recapitulated the protein trafficking defects, lipid storage, and response to mo56Hc exhibited by human cells expressing I1061T NPC1. These tools established a paradigm for testing and validation of proteostatic therapeutics as an important step towards the development of disease-modifying therapies.
Details
- Title: Subtitle
- Mutant induced neurons and humanized mice enable identification of Niemann-Pick C1 proteostatic therapies
- Creators
- Ruth D Azaria - University of MichiganAdele B Correia - University of MichiganKylie J Schache - University of MichiganManuela Zapata - University of Illinois ChicagoKoralege C Pathmasiri - University of Illinois ChicagoVarshasnata Mohanty - University of Illinois ChicagoDharma T Nannapaneni - University of Notre DameBrandon L Ashfeld - University of Notre DamePaul Helquist - University of Notre DameOlaf Wiest - University of Notre DameKenji Ohgane - Ochanomizu UniversityQingqing LiRoss A Fredenburg - University of Notre DameBrian Sj Blagg - University of Notre DameStephanie M Cologna - University of Illinois ChicagoMark L Schultz - University of IowaAndrew P Lieberman - University of Michigan
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.9(20), e179525
- DOI
- 10.1172/jci.insight.179525
- PMID
- 39207850
- PMCID
- PMC11530122
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- NIH: R01 NS122746, K01 DK124450, R01 NS114413, R01 NS124784 NSF CAREER: 2143920 JSPS KAKENHI: JP17K15487, JP20K15949
We thank Xiaochun Li and Tao Long for the gift of recombinant NPC1 protein used in these studies. This work was funded by the NIH (R01 NS122746 to APL; K01 DK124450 to MLS; R01 NS114413 and R01 NS124784 to SMC) , NSF CAREER 2143920 to SMC, Niemann-Pick Canada (to MLS and RDA) , Hope for Marian (to MLS) , the University of Pennsylvania Orphan Disease Center in partnership with the Andrew Coppola Foundation (to MLS) , Support for Accelerated Research for Niemann-Pick Type C (to MLS, APL, and SMC) , JSPS KAKENHI (JP17K15487 and JP20K15949 to KO) , and the Ara Parseghian Medical Research Foundation (to MLS, APL, RAF, PH, and BSJB) .
- Language
- English
- Electronic publication date
- 08/29/2024
- Date published
- 10/22/2024
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9984701859602771
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