TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy is a new family of disorders whose classification originated with the discovery of cytoplasmic and nuclear inclusions composed of ubiquitinated, hyperphosphorylated TDP-43 in a subset of individuals with the neurodegenerative diseases Frontotemporal Dementia (FTD) and Amytrophic Lateral Sclerosis (ALS). TDP-43 inclusions have now been observed in a group of secondary TDP-proteinopathies including Alzheimer's Disease (AD), Dementia with Lewy Bodies (DLB), Pick Disease (PiD), and hippocampal sclerosis. Mutations in the TARDBP gene which encodes TDP-43 have now been associated with both sporadic and familial cases of pure ALS. Additionally, mutant TDP-43 has been implicated in a small number of individuals presenting with frontotemporal lobar degeneration with amyotrophic lateral sclerosis (FTLD-ALS) or with pure FTD. While similar mutations have not been identified in secondary TDP-43 proteinopathies, it is now clear that TDP-43 can directly lead to neurotoxicity, at least in the context of mutation. Post-translational generation of C-terminal fragments (CTF) of TDP-43 is key feature of the disease with the 25kD CTF of TDP-43 being prominently found in a number of TDP-43 proteinopathies. The lack of mouse models of TDP-43 aggregation and neurotoxicity currently prevents the in vivo testing of potential therapies directed against TDP-43 proteinopathies. Our overall goal of this proposal is to generate a mouse model of TDP-43 proteinopathy which will serve as an invaluable tool in drug development for ALS, FTD, and secondary TDP-43 proteinopathies.
Aim 1 : To generate a mouse model of TDP-43 neurotoxicity mediated by the inducible expression of 25kD CTF TDP-43 protein.
Aim 2 : To identify which aspects of TDP-43 proteinopathy may be targets for therapeutic intervention.
Mutations in the TARDBP gene, encoding the TDP-43 protein, have recently been implicated in amyotrophic lateral sclerosis as well as a few cases of frontotemporal dementia. Importantly, abnormal inclusions of TDP-43 protein are common features in a number of neurodegenerative diseases including up to 50% of Alzheimer's Disease cases. There are currently no mouse models for TDP-43 pathology or neurotoxicity. We propose to make a mouse model for diseases characterized by TDP-43 pathology to speed therapy development and validation.
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