Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells
Open accessAbstract
Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease.
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Cholesterol accumulation in lysosomes impairs lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.
“Cholesterol accumulation in lysosomes has been shown to impair lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.15”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [15]
The Results section on the NPC1 mutation reports both cholesterol accumulation and impaired autophagic flux, but says that depleting cholesterol did not rescue the autophagy defect. It instead links the defect to loss of NPC1 function, contrary to the claimed causal role of cholesterol accumulation in NPC. The paper does not specifically report impaired autophagy-mediated mitochondrial degradation. (LLM, conf=0.85)
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Self-citationSREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
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“Chemical Compounds Autophagic flux in NPC1 iPSC-derived cells was assessed using a saturating concentration of bafilomycin A1 (BafA1) clamping LC3-II/autophagosome degradation (Klionsky et al., 2012).”
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- Authors
- Maetzel, D., Sarkar, S., Wang, H., Abi-Mosleh, L., Xu, P., Cheng, A. W., Gao, Q., Mitalipova, M., & Jaenisch, R.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- The University of Texas Southwestern Medical Center (US)
- Skolkovo Institute of Science and Technology (RU)
- Corresponding author
- Jaenisch, Rudolf
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 2
- Issue
- 6
- Pages
- 866-880
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC4050353
- OpenAlex
- W2096912149
- Cited by
- 195
- References
- 7
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 14 · 2021: 24 · 2020: 19 · 2019: 13 · 2018: 17 · 2017: 23 · 2016: 29 · 2015: 17 · 2014: 10
- FWCI
- 16.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
- Funders
- Massachusetts Institute of Technology
- National Institutes of Health (2r01ca084198-10)
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Cancer Institute (R01-CA084198, P30CA014051)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Niemann-Pick disease type C, NPC1, induced pluripotent stem cells, TALEN genome editing, cholesterol accumulation, autophagy, autophagic flux, hepatocytes, neurons, carbamazepine, cell type specificity, cytoprotection, lipid storage disease, neurodegeneration
- MeSH terms
- Adult, Autophagy, Cells, Cultured, Child, Child, Preschool, Cholesterol, Humans, Neurons, Hepatocytes, Niemann-Pick Disease, Type C, Induced Pluripotent Stem Cells
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