Frontotemporal dementia (FTD) is the second leading cause of dementia in adults under 65 years of age. About 20% of genetic cases of FTD are caused by mutations in the gene that codes for the protein progranulin (PGRN). The role of PGRN in neurodegenerative diseases is not completely understood. We use fluorescent probes to study patient cells deficient in PGRN to uncover the underlying dysfunction linked to disease pathology. As well, we perform compound screens to discover chemical PGRN mimics to correct cellular dysfunction.<br/><br/>First, this report will present data from our study using a fluorescent probe that measures enzyme activity in FTD patient-derived cells. Second, discovery of compounds that mimic progranulin protein and correct cellular function is presented. We use a multiplex approach with RASL-seq (RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Gen sequencing) technology, which allows us to do a multiplex screen for hundreds of compounds in a 384-well plate format, with multiple gene expression profiles evaluated in each well. Once the hits from this screen are obtained, structure-activity relationship (SAR) analyses and modifications of compounds are done to elucidate and improve their activity.<br/><br/>Overall, this research project aims to develop compounds able to correct cellular dysfunction caused by PGRN deficiency, with the ultimate goal of discovering drugs to cure FTD.

Chemical correction of cellular dysfunction caused by progranulin deficiency in frontotemporal dementia

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.