Neuronal lesions containing either abnormal pathological tau or abnormal pathological TDP-43 protein characterize frontotemporal lobar degeneration (FTLD). How aggregated, ubiquitinated and phosphorylated TDP-43 protein causes neuronal dysfunction and neurodegeneration is unknown. Likewise, the mechanisms of tau toxicity remain incompletely understood, but hyperphosphorylated, aggregated, and oligomeric tau species exhibit neurotoxicity. This work focuses on extending our previous studies of TDP-43 proteinopathy to complete the molecular genetic dissection of the mechanisms causing neurodegeneration in FTLD-tau and FTLD-TDP. In the previous funding period we showed activation of tau tubulin kinase 1 (TTBK1) stimulates the production of phosphorylated TDP-43, which drives neurodegeneration. We also demonstrated that Calcineurin is the major TDP-43 phosphatase responsible for detoxifying phosphorylated TDP-43. Surprisingly, both TTBK1 and calcineurin play a similar role in the genesis of pathological tau protein in disease. Taken together these findings support the premise of this application that common molecular mechanisms may underpin both TDP-43 and tau pathology in FTLD.
The specific aims of this competitive renewal are: 1) Identify genes with protective variants preventing tau or TDP-43 proteinopathy; 2) Conduct comparative analysis of protective genetic variants for impact in molecular mechanisms of neurodegeneration; 3) Assess protective variants for translational potential as therapeutic targets. Completion of the proposed work will enable the development of neuroprotective strategies targeting pathological tau and TDP-43 in FTLD. The experiments proposed here will define new genes and pathways mediating tau and TDP-43 toxicity. The work will also delineate the relationships between the identified genes and pathways to inform development of new therapies for FTLD.

Public Health Relevance

The progressive dementia caused by tau or TDP-43 proteinopathy has no effective treatment, causes severe disability, and leads to premature death. By identifying new genes and pathways controlling tau and TDP-43 proteinopathy, neuroprotective strategies targeting neurodegeneration in FTLD can be developed. With a more complete understanding of the molecular mechanisms at work in FTLD, we hope to advance the development of therapeutic options for both FTLD-tau and FTLD-TDP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064131-12
Application #
9892035
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Cheever, Thomas
Project Start
2009-02-15
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108
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Liachko, Nicole F; McMillan, Pamela J; Guthrie, Chris R et al. (2013) CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration. Ann Neurol 74:39-52

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