# RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $387,500

## Abstract

Abstract
 Maintenance of RNA homeostasis involves a dynamic balance between RNA synthesis and turnover.
This balance is critical for transcriptionally active cells such as neurons, as disruptions to any individual
component can lead to RNA misprocessing and cell death. Our preliminary evidence indicates that deficiencies
in RNA decay represent a fundamental and heretofore unrecognized mechanism driving neuronal dysfunction
and death in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar
degeneration (FTLD). Our goals with this proposal are to elucidate the role of RNA decay in the pathogenesis
of ALS and FTLD, and investigate a unique and promising therapeutic strategy affecting RNA decay. Based
upon the results of initial studies, we propose that in ALS and the most common subtype of FTLD,
characterized by neuronal deposits of the RNA binding protein TDP43, RNA homeostasis is disrupted by an
inappropriate interaction between TDP43 and the RNA helicase UPF1, ultimately resulting in
neurodegeneration. We will test this model by i) determining the impact of the TDP43-UPF1 interaction on
neuronal survival and RNA decay, ii) evaluating if deficient RNA decay is sufficient and/or necessary for
pathologic TDP43 deposition in neurons, and iii) assessing whether UPF1 expression improves neuronal
survival by restoring TDP43 and RNA homeostasis. We will pursue these aims using a combination of
longitudinal single-cell microscopy of human neurons derived from ALS and FTLD patients, CRISPR/Cas9
genome editing and high-throughput sequencing of pulse-labeled RNA. The multifaceted approach proposed
here promises to uncover key pathways controlling neuronal survival in healthy cells and in those affected by
ALS and FTLD, and will bring us one step closer to achieving our long-term goal of developing an effective
treatment for these and other relentlessly progressive neurodegenerative disorders.

## Key facts

- **NIH application ID:** 9973175
- **Project number:** 5R01NS097542-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sami Barmada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973175

## Citation

> US National Institutes of Health, RePORTER application 9973175, RNA decay in amyotrophic lateral sclerosis and frontotemporal lobar degeneration (5R01NS097542-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9973175. Licensed CC0.

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