# Understanding the Role of RNA Surveillance Mechanisms in Neuropathogenesis during Zika Virus Infection

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $28,196

## Abstract

Project Summary/Abstract
Zika virus was responsible for the 2015 outbreak of microcephaly in Brazil. A concerted worldwide
research effort began to study Zika virus and its impacts on fetal neurodevelopment. These initial studies
discovered that Zika virus was capable of infecting neural progenitor cells, leading to the disruption of
proliferation and differentiation of these cells. However, the molecular mechanisms underlying the
disease caused by Zika virus have yet to be elucidated. The Ott lab recently described the interaction of
Zika virus with the Non-sense Mediated Decay pathway, an RNA surveillance pathway responsible for
destroying aberrant mRNAs, in neural progenitor cells. However, this pathway also plays an important
role in cellular homeostasis and neurodevelopment due to the its ability to regulate a significant portion of
the transcriptome. In this first study, the Ott lab found that Zika virus induced disruption of the NMD
pathway. Interactions between the viral capsid protein and Upframeshift Protein 1 (UPF1), the master
regulator of the Nonsense Mediated Decay pathway, was defined and showed this interaction led to the
nuclear degradation of UPF1. Lastly, UPF1 was shown to be a viral restriction factor and knockdown of
this factor enhanced permissivity of neural progenitor cells to infection. The initial study set the
groundwork for future studies, but many open questions remain. I propose to study the mechanism by
which UPF1 is degraded during infection and what are the downstream consequences of Nonsense
Mediated Decay disruption in neural progenitor cells. Preliminary data shows that UPF1 degradation by
ZIKV capsid can be rescued by proteasomal inhibition. Furthermore, we also know that 96 previously
defined UPF1 targets are upregulated during infection. Therefore, in Aim 1 I propose to study UPF1
degradation during infection of neural progenitor cells to better elucidate the mechanism by which Zika
virus inhibits UPF1 function. In Aim 2, I will describe the downstream impacts that the aforementioned
UPF1 disruption has on neural progenitor cell capabilities, including proliferation and differentiation, by
studying the specific transcripts that are stabilized during infection. This approach will provide
mechanistic detail on how Zika virus causes disease in a relevant cellular model system. Furthermore,
the study of the Nonsense Mediated Decay pathway provides more detail on an RNA surveillance
pathway that is necessary for neurodevelopment. Ultimately, this work could present novel pathways for
the development of future therapeutic interventions for microcephaly.

## Key facts

- **NIH application ID:** 9942264
- **Project number:** 5F31NS113432-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kristoffer E Leon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $28,196
- **Award type:** 5
- **Project period:** 2019-07-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942264

## Citation

> US National Institutes of Health, RePORTER application 9942264, Understanding the Role of RNA Surveillance Mechanisms in Neuropathogenesis during Zika Virus Infection (5F31NS113432-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942264. Licensed CC0.

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