# Identifying the function of alternatively spliced TDP43 isoforms and contribution to disease

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,600

## Abstract

PROJECT SUMMARY
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related, often comorbid,
neurodegenerative disorders with no available disease-modifying therapies. In over 95% of ALS patients, and
50% of FTD patients, affected neurons exhibit cytoplasmic mislocalization and accumulation of TDP43
(transactive response element DNA/RNA binding protein, 43 kDa). Mutations in TARDBP, the gene encoding
TDP43, also cause familial forms of ALS and FTD, highlighting an integral contribution of TDP43 to these
conditions. Even so, the mechanisms underlying TDP43 mislocalization in disease remain unclear.
Recent evidence from our laboratory suggests that TDP43 mislocalization may be due to the production of
alternatively spliced, shortened (s)TDP43 isoforms that are actively exported from the nucleus and prone to
aggregation. sTDP43 isoforms are also evolutionarily conserved, but their regulation and function remain
fundamentally unknown.
This proposal seeks to elucidate the distinct function of sTDP43 isoforms and their potential contribution to
disease by (i) defining the native transcript and protein interactors for sTDP43; and (ii) investigating a potential
role for sTDP43 in regulating RNA stability. In so doing, these studies may reveal new pathways responsible for
TDP43 mislocalization and neurodegeneration ALS and FTD. Additionally, it will enable me to develop essential
skills in bioinformatics, proteomics, experimental design, data analysis, and scientific communication that will be
critical for my success in my intended career as an independent investigator focused on the molecular
underpinnings of neurodegeneration.

## Key facts

- **NIH application ID:** 10993093
- **Project number:** 5F31NS134123-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Megan Dykstra
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,600
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993093

## Citation

> US National Institutes of Health, RePORTER application 10993093, Identifying the function of alternatively spliced TDP43 isoforms and contribution to disease (5F31NS134123-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10993093. Licensed CC0.

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