Modeling Progranulin hypomorphism for FTD in mice

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DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is the 2nd most common clinical dementia after Alzheimer's disease. FTD results from neuronal degeneration in the frontal temporal cortices, leading to a loss of functions in these brain regions. The main clinical symptoms are difficulty in modifying behavior based on social demands, lack of inhibition, impulsive and compulsive acts, lack of concern for others, deterioration of personal hygiene and progressive language dysfunction. It differs from Alzheimer's disease in that the disease begins with mild or no memory loss. Only until the late stage of the disease does memory loss emerge. About 40-50% of FTD cases have a family history and are caused by genetic mutations. The genes whose mutation have been identified to cause FTD are microtubule-associated protein tau (MAPT), charged multivesicular body protein 2B (CHMP2B), vasolin-containing protein (VCP) and progranulin (PGRN). Mutations in progranulin gene are the most recently identified and have been shown to be a common genetic cause for FTD. Together with mutations in tau, it accounts more than half of the familial FTD cases. Genetic studies have implicated that the mutations cause loss of progranulin function and the disease is a result of haploinsufficiency. To study the disease mechanism, we propose to apply a newly developed transgenic RNAi approach to create a mouse FTD model by silencing the progranulin gene using an inducible miRNA-expressing construct. If successful, we will generate a new animal model for FTD, which can be used to investigate the neurodegeneration mechanism and test therapeutic strategies for this disease. We seek to establish a mouse model for frontotemporal dementia (FTD) by inhibition of progranulin expression using RNAi. Progranulin mutations cause human FTD, which is a neurodegenerative disease that changes people's personality, ability to plan and behave appropriately in social settings. If successful, our work will establish the first animal model for this disease, which can be used for studying neurodegeneration mechanisms and testing therapeutic strategies.