# Investigating calcineurin regulation of pathological TDP-43 phosphorylation in ALS

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

## Abstract

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease
characterized by degeneration of motor neurons in the brain and spinal cord, resulting in neurogenic muscle
wasting, paralysis, and death. Nearly 95% of ALS cases have pathology featuring phosphorylated
inclusions of the TDP-43 protein in neurons and glial cells. Furthermore, mutations in the gene coding for
TDP-43 have been shown to cause some cases of ALS, indicating normal TDP-43 is critical for neuronal
health. Phosphorylation of TDP-43 reduces its turnover, increases its aggregation, and promotes
neurotoxicity and neurodegeneration. Recent work has identified the phosphatase calcineurin as a key
regulator of phosphorylated TDP-43 (pTDP) accumulation. By dephosphorylating pTDP, calcineurin
reduces levels of neurotoxic pTDP and protects against disease phenotypes, including neurodegeneration.
An understanding of the mechanisms controlling TDP-43 pathology in ALS is critical to the design of
neuroprotective strategies.
 This proposal describes experiments exploring the cellular and molecular changes that promote
TDP-43-targeted calcineurin phosphatase activity, with a focus on the development of therapeutic
interventions for the treatment of ALS. This work will 1) elucidate mechanisms controlling calcineurin
activation and pTDP clearance, 2) evaluate activation of calcineurin as a novel therapeutic strategy for the
clearance of pTDP, 3), provide new information about cellular recovery following neurotoxic stress, and 4)
may provide additional targets for therapeutic intervention. Completion of this work will advance
understanding of the disease processes underlying ALS and provide preclinical validation of a new
therapeutic approach.

## Key facts

- **NIH application ID:** 9815316
- **Project number:** 5I01BX004044-02
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Nicole Faron Liachko
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815316

## Citation

> US National Institutes of Health, RePORTER application 9815316, Investigating calcineurin regulation of pathological TDP-43 phosphorylation in ALS (5I01BX004044-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815316. Licensed CC0.

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