# Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2020 · —

## Abstract

TAR DNA-binding protein 43 kDa (TDP-43) is the major aggregating disease protein in amyotrophic
lateral sclerosis (ALS). Over 90% of ALS cases exhibit pathological lesions containing detergent
insoluble deposits of phosphorylated, truncated, and ubiquitinated TDP-43 protein. TDP-43
phosphorylated at S409/410 (pS409/410) is the most consistent, robust, and specific neuropathological
feature of ALS suggesting a phosphorylated TDP-43 (pTDP) mediated cascade of neurotoxicity.
Furthermore pTDP has been shown to influence the aggregation of TDP-43 in cultured cells and in
human ALS cases. Our previous work demonstrated pS409/410 TDP-43 mediates motor neuron
toxicity of familial ALS-causing TDP-43 mutations. Kinases regulating TDP-43 phosphorylation present
an attractive target for therapeutic intervention in ALS. We have identified a well-conserved TDP-43-
active kinase with translational potential known as tau tubulin kinase 1 (TTBK1). Identification of brain
penetrant TTBK1 inhibitors may ultimately provide a viable drug development strategy. We
hypothesize that increased TDP-43 phosphorylation drives motor neuron degeneration in ALS and that
blocking pTDP accumulation by inhibiting TTBK1 will protect against TDP-43 mediated
neurodegeneration in ALS. Three integrated specific aims are proposed: 1) Identification of TTBK1
selective kinase inhibitors. 2) Optimization of TTBK1 selective inhibitors and validation of selective
compounds in a cellular model of pTDP accumulation. 3) Validation of the role of TTBK1 in the formation
of pTDP using TTBK1 knockout mice and an existing transgenic model of TDP-43 proteinopathy. The
studies proposed here will set the stage for development of TTBK1 selective inhibitors as a candidate
therapeutic approach for ALS.

## Key facts

- **NIH application ID:** 9898277
- **Project number:** 5I01BX003755-04
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Brian C. Kraemer
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898277

## Citation

> US National Institutes of Health, RePORTER application 9898277, Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS (5I01BX003755-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898277. Licensed CC0.

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