Zachary C Rosenthal, Daniel M Fass, N Connor Payne, Angela She, Debasis Patnaik, Krista M Hennig, Rachel Tesla, Gordon C Werthmann, Charlotte Guhl, Surya A Reis, Xiaoyu Wang, Yueting Chen, Michael Placzek, Noelle S Williams, Jacob Hooker, Joachim Herz, Ralph Mazitschek, Stephen J Haggarty
Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells...
April 20, 2024: Scientific Reports