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Protein Deimination in Protein Misfolding Disorders: Modeled in Human Induced Pluripotent Stem Cells (iPSCs)

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Protein Deimination in Human Health and Disease

Abstract

Neurodegenerative diseases present an enormous challenge to medicine, and the need for biomarker discovery and novel drug-directed strategies are thus of high priority. A common disease feature is the accumulation of misfolded proteins, which leads to cellular stress responses, including raised calcium levels, and results in neuronal death. Peptidylarginine deiminases (PADs) are calcium-activated enzymes that cause structural changes and misfolding in target proteins that further contribute to neuronal death. As we have previously shown that pharmacological PAD inhibition is neuroprotective in animal models of acute CNS injury, we propose that PAD inhibitors offer a novel interceptive treatment to reduce neuronal damage caused by accumulative PAD-mediated protein misfolding in neurodegenerative disease progression. The use of human induced pluripotent stem cell (iPSC) cultures may prove an invaluable tool to elucidate the contribution of protein deimination to neurodegenerative pathologies and to test the feasibility of selected PAD inhibitors to slow down disease progression. We have utilized fibroblast-derived iPSC neuronal cultures from patients carrying neurodegenerative disease-causing mutations for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD) and found increased levels of deiminated proteins compared to non-mutated control neurons. Our findings support that human iPSC cultures can be used as a functional tool for modeling protein deimination in neurodegenerative disease and may be useful in future testing of drug-directed PAD inhibitors.

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Authors and Affiliations

  1. University of Westminster, Department of Biomedical Sciences, London, W1W 6UW, UK

    Sigrun Lange

  2. UCL School of Pharmacy, London, WC1N 1AX, UK

    Sigrun Lange

  3. UCL Institute of Neurology, Department of Molecular Neuroscience, London, WC1N 3BG, UK

    Selina Wray, Mike Devine, Mar Matarin & John Hardy

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  1. Sigrun Lange
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  2. Selina Wray
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  3. Mike Devine
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  4. Mar Matarin
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  5. John Hardy
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Correspondence to Sigrun Lange .

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Editors and Affiliations

  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA

    Sanjoy K. Bhattacharya

  3. Department of Biochemistry and Molecular Pharmacology, UMASS Medical School, Worcester, Massachusetts, USA

    Paul R. Thompson

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Lange, S., Wray, S., Devine, M., Matarin, M., Hardy, J. (2017). Protein Deimination in Protein Misfolding Disorders: Modeled in Human Induced Pluripotent Stem Cells (iPSCs). In: Nicholas, A., Bhattacharya, S., Thompson, P. (eds) Protein Deimination in Human Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-58244-3_13

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