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Analyzing Mitochondrial Transport and Morphology in Human Induced Pluripotent Stem Cell-Derived Neurons in Hereditary Spastic Paraplegia
Published on: February 9, 2020
Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient
Jung-Il Chae1, Dong-Wook Kim, Nayeon Lee
1Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 project, Chonbuk National University, Jeonju 651-756, Korea.
Insights
Huntington
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a genetic neurodegenerative disorder caused by CAG repeat expansion in the HTT gene.
- Induced pluripotent stem cells (iPSCs) from HD patients offer a model for studying disease mechanisms.
Purpose of the Study:
- To investigate the proteomic differences between HD-iPSCs and normal cells.
- To identify potential therapeutic targets for Huntington's disease.
Main Methods:
- Comparative proteomic analysis of normal human embryonic stem cells (hESCs), iPSCs, and HD-iPSCs.
- Identification and characterization of differentially expressed proteins.
Main Results:
- 26 proteins were found to be up- or down-regulated in HD-iPSCs.
- HD-iPSCs showed increased susceptibility to oxidative stress, with affected SOD1 and Prx families.
- Up-regulation of BTF3 induced ATM and activated the p53 apoptotic pathway.
- Reduced cytoskeleton-associated proteins suggested impaired neuronal differentiation.
Conclusions:
- HD-iPSCs serve as a valuable cellular model for understanding HD pathogenesis and neurodegeneration.
- Identified proteins represent potential therapeutic targets for Huntington's disease.
Abstract:
HD (Huntington's disease) is a devastating neurodegenerative genetic disorder caused by abnormal expansion of CAG repeats in the HTT (huntingtin) gene. We have recently established two iPSC (induced pluripotent stem cell) lines derived from a HD patient carrying 72 CAG repeats (HD-iPSC). In order to understand the proteomic profiles of HD-iPSCs, we have performed comparative proteomic analysis among normal hESCs (human embryonic stem cells; H9), iPSCs (551-8) and HD-iPSCs at undifferentiated stages, and identified 26 up- and down-regulated proteins. Interestingly, these differentially expressed proteins are known to be involved in different biological processes, such as oxidative stress, programmed cell death and cellular oxygen-associated proteins. Among them, we found that oxidative stress-related proteins, such as SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families are particularly affected in HD-iPSCs, implying that HD-iPSCs are highly susceptible to oxidative stress. We also found that BTF3 (basic transcription factor 3) is up-regulated in HD-iPSCs, which leads to the induction of ATM (ataxia telangiectasia mutated), followed by activation of the p53-mediated apoptotic pathway. In addition, we observed that the expression of cytoskeleton-associated proteins was significantly reduced in HD-iPSCs, implying that neuronal differentiation was also affected. Taken together, these results demonstrate that HD-iPSCs can provide a unique cellular disease model system to understand the pathogenesis and neurodegeneration mechanisms in HD, and the identified proteins from the present study may serve as potential targets for developing future HD therapeutics.
