Neurodegenerative diseases, including Alzheimer's and Parkinson's, present an increasing challenge to society due to an ageing population. Common disease features are misfolded proteins, which lead to cellular stress responses such as elevated calcium levels and result in neuronal death. This project focuses on a group of calcium-dependent enzymes, peptidylarginine deiminases (PADs), that cause "protein deimination" when calcium levels rise. This results in further protein misfolding, inflammatory responses, effect on the regulation of the cell's genes and contributes to neuronal death. Increased levels of "deiminated" proteins are observed in post-mortem human brain samples of Alzheimer's and Parkinson's patients and we found that animal models of Alzheimer's disease demonstrate increased levels of PAD enzymes during disease progression. We have previously demonstrated a novel neuro-protective role for an experimental PAD-inhibiting drug in animal models of central nervous system injury. The same PAD inhibitor has also shown efficacy in animal models of rheumatoid arthritis and Chron's disease. We propose that refined PAD inhibitors offer a novel interceptive treatment route, and that their fuction will be translatable to reduce neuronal damage in neurodegenerative disease progression. To demonstrate this in a human model, we will use the novel tool of induced pluripotent stem cell cultures (iPSCs), where neuronal cells are produced by reprogramming skin cells of patients carrying the neurodegenerative disease causing mutations. The advantage is that novel drugs can be tested and optimized in human rather than animal models and that we can reproduce pathologies that take years to accumulate in the brain, in a relatively short time. Our preliminary results on these iPSC derived neurons show that certain neurodegenerative mutations display increased protein deimination compared to controls. This project will pave the way for novel drug development and strategies to increase the life quality and healthy ageing of sufferers of progressive neurological disease.