RNA Spliceosome Modulator GEX1A: A Novel Targeted Therapeutic for Frontotemporal Dementia
Student: Laura Shute, 2015-2016
Sponsor: Prof. Rich Taylor - Chemistry and Biochemistry, Notre Dame, IN
Frontotemporal dementia (FTD) is a terminal pre-senile neurodegenerative disorder which produces behavioral and cognitive decline in up to 30,000 Americans aged 45-70. Progranulin haploinsufficiency, a highly penetrant mutation expressed in the majority of FTD cases, causes pathological TDP-43 inclusions, neuron death, and atrophy in the brain’s frontal and temporal lobes. This damage to the brain’s language and personality centers manifests as socially unacceptable behavior, uncharacteristic mood swings, and progressive aphasia, leading to death within 5 years of diagnosis. In vitro progranulin knockout and upregulation rescue studies have identified progranulin expression as an important therapeutic target for FTD. This project explores the potential of GEX1A, an RNA splicing modulator, to treat FTD via progranulin upregulation in contrast to current psychological symptom management treatment strategies. GEX1A binds to SAP 155 protein and prevents U2 snRNP from binding to the intron branch site near the 3’ splice site, leading to selection of inappropriate 3’ splice sites and resulting alternative RNA splicing. The Taylor lab is exploring the effect of GEX1A, already characterized as a promising therapy against the liposomal storage disorder Niemann-Pick Type C, on progranulin expression levels as a novel therapy for frontotemporal dementia.