# Investigating the mechanism of UPF1-mediated rescue of TDP-43-based models of ALS and FTD

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $38,495

## Abstract

PROJECT SUMMARY
 Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive
loss of upper and lower motor neurons, leading to paralysis and death. There are no available disease-modifying
drugs. In 95% of individuals with ALS, affected neurons exhibit cytoplasmic accumulation of TDP-43 (transactive
response element DNA/RNA binding protein, 43 kDa). TDP-43 is a ubiquitously expressed splicing factor that is
normally localized to the nucleus. In cellular and animal model systems, overexpression of TDP-43 results not
only in neurodegeneration, but also TDP-43 cytosolic mislocalization and aggregation, recapitulating key
pathologic changes seen in humans. Mutations in the genes encoding TDP-43 (TARDBP) and several similar
RNA-binding proteins (RBPs) (e.g. FUS, HNRNPA2B1, MATR3) cause familial ALS as well as the related, often
comorbid disease frontotemporal dementia (FTD). How aberrant RBP function may cause ALS and FTD is an
ongoing area of research; nevertheless, several pieces of evidence suggest that global disruption of RNA splicing
and stability is a central theme.
 We and others determined that overexpression of the RNA helicase Up-frameshift 1 (UPF1) ameliorates
toxicity in both in vivo and in vitro models of TDP43 and FUS toxicity. This proposal seeks to elucidate the
mechanism of UPF1-mediated neuroprotection, particularly in models of TDP-43 toxicity. UPF1 is an obligate
component of nonsense-mediated decay (NMD), a vital RNA surveillance program. Since the toxicity of TDP-43
dysregulation is strongly linked to its ability to bind RNA, the proposal focuses on the potential interactions
between UPF1 and TDP-43 substrates. I hypothesize that UPF1 rescues TDP-43 toxicity by (a) facilitating the
clearance of mispliced TDP-43 targets through NMD, (b) interfering with the ability of TDP-43 to bind RNA, or a
combination of both. These investigations will not only provide me with the opportunity to develop fundamental
scientific skills in experimental design, bioinformatics, and communication, but also promise to deliver new insight
into the therapeutic potential of UPF1-mediated neuroprotection. Ultimately, these opportunities will be
instrumental in my path to independence as a successful neurologist and neuroscientist dedicated to the study
of neurological conditions, disease mechanisms, and therapeutic interventions.

## Key facts

- **NIH application ID:** 10049194
- **Project number:** 5F31NS115257-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nicolas Benjamin Gomez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,495
- **Award type:** 5
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049194

## Citation

> US National Institutes of Health, RePORTER application 10049194, Investigating the mechanism of UPF1-mediated rescue of TDP-43-based models of ALS and FTD (5F31NS115257-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10049194. Licensed CC0.

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