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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Sutherland, Margaret L
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University of Florida
Schools of Medicine
United States
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D'Alton, Simon; Altshuler, Marcelle; Cannon, Ashley et al. (2014) Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling. PLoS One 9:e86513
Cannon, Ashley; Yang, Baoli; Knight, Joshua et al. (2012) Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. Acta Neuropathol 123:807-23
Xu, Ya-Fei; Zhang, Yong-Jie; Lin, Wen-Lang et al. (2011) Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener 6:73