Modeling TDP-43 Dysfunction in vivo

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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% 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). How these mutant genes cause neuronal degeneration is not known. Common to more than half of the patients is the pathology of ubiquitin-positive inclusions in the cortical neurons. Recently, TDP-43 is identified as a main component in the ubiquitin inclusions. TDP-43 is a ubiquitously expressed nuclear protein that may function in transcription regulation, mRNA splicing and may interact with SMN, whose mutation cause spinal muscular atrophy. In FTD patients, TDP-43 is reduced in the nuclei of the neurons that have the ubiquitin-positive inclusions, suggesting that its function may be reduced. Interestingly, TDP-43 is also found in the ubiquitin inclusions in motor neurons of patients with amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, suggesting that FTD and ALS may share common pathogenic mechanisms. To investigate the function of TDP-43 and its role in FTD, we propose to apply a newly developed transgenic RNAi approach to create a mouse model of TDP-43 hypomorphism. 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. PUBLIC HEALTH RELEVANCE TDP-43 forms protein aggregates in FTD and ALS, two fatal neurodegenerative diseases without a cure. The aggregation of TDP-43 can compromise the normal function of TDP-43. We seek to establish a mouse model with compromised TDP-43 function using RNAi. This model will test whether reduced TDP-43 function can cause neurodegeneration similar to what occurs in FTD and ALS and will be useful for studying neurodegeneration mechanism in FTD and ALS.