110. Epigenetic Treatments for Dementia: HDAC Inhibitors & Beyond

Abstract

Frontotemporal dementia (FTD) is a clinical syndrome, characterized by progressive deterioration of decision-making abilities, control of behavior, and language. A frequent cause of FTD is loss-of-function mutations in the GRN gene encoding progranulin (PGRN), a secreted glycoprotein with growth factor-like and immunomodulatory activities. One potential strategy to correct the pathological consequences of GRN haploinsufficiency is to increase the expression from the remaining functional allele. To this end, inhibitors of histone deacetylases (HDACs), have been shown to be induce PGRN expression. However, the precise molecular mechanisms behind their regulation of PGRN, including if they directly affect histone acetylation within the GRN locus, which HDACs are the relevant targets, and their optimal kinetic profile, has yet to be elucidated.