Chapter title | Protein Deimination in Protein Misfolding Disorders - Modelled in Human induced Pluripotent Stem Cells (iPSCs) |
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Authors | Lange, S., Wray, S., Devine, M., Matarin, M. and Hardy, J. |
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Editors | Nicholas, A.P., Battacharya, S.K. and Thompson, P.R. |
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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 modelling protein deimination in neurodegenerative disease and may be useful in future testing of drug directed PAD-inhibitors |
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Keywords | induced pluripotent stem cells (iPSCs), deimination, PADs, citH3, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), Alzheimer’s disease (AD) |
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Book title | Protein Deimination in Human Health and Disease |
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Page range | 227-239 |
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Year | 2017 |
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Publisher | Springer |
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Publication dates |
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Published | 21 Sep 2017 |
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Place of publication | Cham, Switzerland |
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ISBN | 9783319582436 |
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Digital Object Identifier (DOI) | https://doi.org/10.1007/978-3-319-58244-3_13 |
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Web address (URL) | http://www.springer.com/gp/book/9783319582436 |
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