Interactions between progranulin insufficiency and TDP-43

PROJECT SUMMARY Frontotemporal Dementia (FTD) is a major cause of early onset dementia and patients can develop a wide range of symptoms including behavioral changes and language impairments. Heterozygous mutations in the progranulin gene (GRN) result in haploinsufficiency of the protein and cause FTD with TDP-43 pathology. TDP- 43 is a RNA binding protein that, in disease states, mislocalizes to the cytoplasm and forms insoluble inclusions. All FTD-GRN patients develop TDP-43 pathology, however it is not understood how partial loss of progranulin promotes TDP-43 mislocalization and aggregation. Progranulin heterozygous mice (Grn+/–) are the genetic model of FTD-GRN and develop age dependent behavioral abnormalities, but do not develop TDP-43 pathology. This project uses Grn+/– mice crossed with human TDP-43 transgenic mice (hTDP+) to investigate whether progranulin insufficiency results in TDP-43 dysregulation. Initial studies of the Grn+/–:hTDP+ mice show a severe impairment of social dominance behavior and an increase in insoluble TDP-43 in the medial prefrontal cortex (mPFC), a region critical for normal social dominance behavior. Additionally, preliminary studies suggest that there may be impairments in TDP-43-dependent splicing and autoregulation in the Grn+/–:hTDP+ mice. My overarching hypothesis is that the synergistic effects of progranulin insufficiency and TDP-43 overexpression on social dominance behaviors are due to TDP-43 dysregulation in the mPFC. This proposal will test two aims: 1) Determine if progranulin insufficiency promotes TDP-43 mislocalization and dysregulation in the mPFC and 2) Determine if impaired social dominance behaviors are driven by hTDP expression in the mPFC. As behavioral changes are a major feature of FTD, determining the role of TDP-43 in the mPFC could be vital for developing future therapeutics. The overall goal of the training plan is to instruct the PI in neurodegeneration research and provide a solid foundation for a successful career as a physician scientist. A project based in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.