Fluorescent IRE sensor for PD drug discovery

SUMMARY Parkinsonandapos s diseasePDis a debilitating neurodegenerative disease that affects aboutof the population over the age ofThe pathological hallmark of PD is the presence of intracellular protein aggregates that cause the degeneration and then death of dopaminergic neurons in the substantia nigraThe presynaptic proteinsynuclein was found to be the main component of Lewy bodies andsynuclein aggregation is believed to be the key event in PD pathogenesisPast drug discovery efforts have been focused on preventingsynuclein aggregation or increasingsynuclein clearanceHoweveroverexpression and knockdown studies in cell lines and animal models showed that altering intracellularsynuclein protein levels can also regulate PD pathologyThese results suggest thatsynuclein translation is a significant yet under explored target for PD drug discoveryA putative iron responsive elementIREthat exhibited high sequence and structural similarities with the ferritin IRE was found in the distalandaposuntranslated region ofsynuclein mRNA and studies suggest that this IRE plays a critical role in regulatingsynuclein translationThus farthere is no high throughput drug discovery methods that can interrogate drug binding directly to RNA structures that control protein translationThis is needed to bypass artifact prone protein reporters that are typically used to study translation inhibitorsThereforethis phase I SBIR application aims to develop a fluorescence sensor that monitors drug binding to IREs and can enable high throughput drug screens for compounds that specifically targetsynucleinandapos s IRE and ultimately result in lead compounds that could eventually be developed into inhibitor ofsynuclein protein synthesis PROJECT NARRATIVE Parkinsonandapos s disease is a debilitating neurodegenerative disease that is currently without a cureMost drug discovery efforts have been focused on preventingsynuclein aggregation or increasingsynuclein clearanceWe aim to develop a RNA structure based sensor that enables the screening of drugs that bind directly to thesynuclein mRNA and inhibit its protein expression