Frontotemporal dementia is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. Members of our team recently reported that loss-of-function mutations in the gene for a protein called progranulin cause 25 percent of frontotemporal dementia cases. Of these mutations, 30-40 percent are “nonsense mutations” that act as stop signs to prematurely end a process required to produce normal progranulin. When progranulin production ends too early, it leads to a shortened protein that cannot carry out the normal brain functions, eventually leading to dementia in the sixth decade.
The goal of this project is to investigate small molecule combinations that can bypass the abnormal “stop sign” in the progranulin gene, increasing the normal production of this important protein. The small molecule combinations will be refined and optimized to find the most effective combination. This approach, also referred to as “suppression of nonsense mutations”, offers the possibility of developing a new drug for patients with frontotemporal dementia cause by a progranulin mutation. The team also plans to develop a mouse model of frontotemporal dementia to test the small molecule combinations in a living organism.