Chemical Neurobiology of Progranulin-Deficient Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a presenile dementia presenting with a variety of clinical phenotypes arising from Frontotemporal Lobar Degeneration (FTLD), a family of neurodegenrative pathologies with a predeliction for the frontal, insular, and anterior temporal lobes. Known autosomal dominant causes of FTLD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. As mRNA from the mutated allele of GRN is degraded via nonsense-mediated mRNA decay mechanisms, one therapeutic avenue for PGRN-deficient FTD is to increase mRNA, and subsequently protein expression, of the ‘wild-type’ (non-mutated) copy of GRN. This dissertation presents the systematic assessment of the abilities of different classes of small molecules to enhance GRN mRNA and PGRN protein expression in human induced pluripotent stem cell (iPSC)-derived neuronal cells. The work explores selectivity and kinetic requirements of histone deacetylase (HDAC) inhibitors to enhance PGRN expression (Chapter 3), defines key epigenetic markers associated with HDAC inhibitor-mediated GRN regulation (Chapter 4), identifies inhibitors of bromodomain and extra-terminal domain containing proteins (BET inhibitors) as a novel class of GRN/PGRN enhancers (Chapter 5), and considers the implications of treatment with other classes of compounds that regulate GRN/PGRN expression (Chapter 6). Finally, the dissertation describes the generation of patient-derived, iPSC models of behavioral variant FTD (bvFTD) using reprogramming technologies that can be used for modeling the pathophysiology and treatment of FTD. Taken together, these findings have implications for studies of the epigenetic and potential cis-regulatory mechanisms controlling GRN expression from the human genome and therefore may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD and other neurodegenerative disorders.