Frontotemporal dementia (FTD) affects an estimated 50,000 Americans and is the second leading cause of dementia in people under 65 years of age. Of the hereditary cases of FTD, about a quarter are caused by a mutation in the gene granulin. This gene codes for the protein progranulin (PGRN) that is involved in many cellular processes. People with granulin mutation have half of PGRN protein, and thus have impaired cellular function, eventually resulting in neurodegeneration, changes in personality, and social behavior. Like other neurodegenerative diseases, FTD resulting from PGRN haploinsuficiency has no cure. Our approach to treatment is to identify a compound that has the same function as progranulin. To identify progranulin mimetics, we utilize RASL-seq (RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing) technology to establish effect of thousands of compounds on gene expression in brain cells that model the disease. Here, we present data from a multiplex screen of 1,400 bioactive compounds. Using this assay, we established a transcriptional difference (mRNA levels) between normal mouse microglia brain cells and those with progranulin genetically removed. After addition of compounds, we analyzed gene expression profiles and ranked compounds by their effectiveness in shifting cells toward normal function. The top 50 compounds were selected for testing in cellular activity assays to further narrow down best candidates that can replace PGRN. We test lysosomal activity using fluorescent agent BMV109, as well as cellular inflammatory response to endotoxins. Top five compound hits from these assays are further examined for structure-activity relationships (SAR) in order to modify and improve their activity. The ultimate goal of this project is to identify compound hits and develop them into lead compounds for curing Frontotemporal dementia.

Identifying compounds that restore normal cellular function in Frontotemporal dementia caused by progranulin haploinsufficiency

256th National Meeting (2018)

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