# Developing Neuroprotective Strategies for Tau and TDP-43 Proteinopathy in FTLD

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2020 · $551,207

## Abstract

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.

## Key facts

- **NIH application ID:** 9892035
- **Project number:** 5R01NS064131-12
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** Brian C. Kraemer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $551,207
- **Award type:** 5
- **Project period:** 2009-02-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892035

## Citation

> US National Institutes of Health, RePORTER application 9892035, Developing Neuroprotective Strategies for Tau and TDP-43 Proteinopathy in FTLD (5R01NS064131-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892035. Licensed CC0.

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