# Understanding the NMD regulatory path from genetic variation to phenotypes

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $298,872

## Abstract

PROJECT SUMMARY
Identifying new molecular mechanisms of Alzheimer's disease (AD) pathogenesis is urgent. Regulation of RNA
processing and translation can play a vital role in AD. Nonsense-mediated mRNA decay (NMD) is a
translation-dependent mRNA surveillance mechanism to degrade error-containing “faulty” transcripts as well as
many naturally occurring “normal” transcripts. Multiple lines of evidence support the essential role of NMD in
neural development, neural homeostasis, and neural degeneration. More recent studies show that deficits in
the overall activity of NMD causally mediate tau-induced neurotoxicity, and the reactivation of NMD in defective
neurons is neuroprotective.
 This supplement application built upon our parent award will systematically investigate the dysregulation of
NMD as a risk factor and possible disease mechanism contributing to AD development. Our parent R01 project
has revealed the genome-wide landscape of genetic variants associated with NMD regulation (i.e., NMD-
QTLs) in the natural population of Genotype-Tissue Expression (GTEx). NMD-QTLs are much more likely to
colocalize with disease SNPs, especially those associated with brain diseases. Brain tissues have distinct
NMD-QTL signatures, particularly the disease-related NMD-QTLs. Notably, among the 1779 nonredundant
AD-associated SNPs reported in the Genome-Wide Association Studies (GWAS) catalog, 111 are NMD-QTLs,
further suggesting an essential role of NMD in AD.
 Guided by promising preliminary data, we hypothesize that systematical analyses of NMD regulation in the
brain using public patient data and omics resources will be critical to dissecting novel mechanisms of AD
pathology. In this supplement, we will integrate NMD dysregulation as a mechanism to explain AD-associated
genetic variants and prioritize causal genes for AD. Successful completion of this project will be the prelude to
understanding the role of NMD in AD.

## Key facts

- **NIH application ID:** 10714885
- **Project number:** 3R01GM137428-04S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Liang Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $298,872
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10714885

## Citation

> US National Institutes of Health, RePORTER application 10714885, Understanding the NMD regulatory path from genetic variation to phenotypes (3R01GM137428-04S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10714885. Licensed CC0.

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