Understanding Frontotemporal Dementia Using Drosophila and iPSC Models

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ABSTRACT Dementia in aging populations poses a major global health challenge in years to come. In addition to Alzheimer’s disease (AD), frontotemporal dementia (FTD) is another major form of presenile dementia caused by focal degeneration of the prefrontal and/or temporal lobes. FTD patients show changes in personality, social behaviors, or language production. Currently, effective treatments for FTD still remain elusive and the underlying pathogenic mechanisms are poorly understood. The identification of many genes whose mutations are associated with FTD offers an exciting entry point. Among them a GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common cause of FTD. This mutation is also the most common genetic cause of amyotrophic lateral sclerosis (ALS), further highlighting the importance of understanding neurotoxicity caused by expanded G4C2 repeats and dipeptide repeat (DPR) proteins translated from both sense and antisense repeat RNAs. In this proposal, we will take advantage of both classical genetics of fruitfly Drosophila and cutting-edge techniques that are applicable to patient neurons differentiated from induced pluripotent stem cells (iPSCs) to identify and characterize potent genetic modifiers of disease phenotypes relevant to C9ORF72-FTD/ALS. These mechanistic studies will help understand molecular pathways involved in these disorders and may also reveal potential effective drug targets for therapeutic interventions.