# Unfolded Protein Response in Drosophila models of Retinitis Pigmentosa

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $420,163

## Abstract

Project Summary
Rhodopsins are G-protein coupled proteins that initiate signal transduction in response to light exposure. There
is significant interest in understanding Rhodopsin homeostasis because dysfunctional Rhodopsins are among
the most frequent causes of Retinitis Pigmentosa (RP), a genetic disorder with age-related retinal degeneration.
Among those associated with RP are Rhodopsin mutants with impaired protein folding properties. Because
Rhodopsins undergo synthesis and folding in the endoplasmic reticulum (ER), such Rhodopsin mutants could
impose stress on this organelle. Those conditions activate an adaptive signaling response that regulates gene
expression, widely referred to as the Unfolded Protein Response (UPR). One particular UPR signaling branch
relevant to this proposal is the one mediated by the ER stress sensor PERK and its downstream effector ATF4.
Among others, UPR signaling induces the expression of genes that help fold or degrade misfolded proteins in the
ER, thereby affecting retinal degeneration in RP. The basic mechanisms of UPR signaling, Rh1 homeostasis,
and retinal degeneration are conserved in Drosophila melanogaster. Specifically, Drosophila ninaE encodes the
Rhodopsin-1 (Rh1) protein expressed in adult eye photoreceptors. A mutant allele of this gene, ninaEG69D, serves
as a model for RP as it imposes ER stress, activates the UPR, and dominantly causes age-related retinal
degeneration. The long-term goal of this project is to harness the genetic and genomic tools of Drosophila to
understand the role of UPR in retinal degeneration. Here, I propose to investigate new UPR signaling branches
that may significantly change our understanding of Rhodopsin homeostasis and retinal degeneration. In Specific
Aims 1 and 2, I propose to re-evaluate the widespread idea that ATF4 is the primary downstream effector of
PERK-mediated UPR. Arguing against this, we recently identified a new sub-branch of the PERK pathway
mediated by Xrp1, a bZIP transcription factor. How Xrp1 is regulated and whether it affects retinal degeneration
remains unclear. We will specifically test the hypothesis that Xrp1 is translationally induced by PERK. We will
determine if such induction affects the course of retinal degeneration and whether Xrp1 requires
heterodimerization partners to regulate some or all downstream target genes. I further propose to identify the
human equivalent of the Xrp1 heterodimer complex. In Aim 3, I propose to investigate a possible link between ER
stress and endosome trafficking in the RP model. Most UPR studies have focused on its role in ER homeostasis.
However, our recent gene expression profiling results reveal that ninaEG69D/+ photoreceptors also induce many
endosomal trafficking regulators. I propose to determine if those endosomal factors are induced by the UPR or
by other unconventional signaling pathways. We will further determine if those pathways affect Rhodopsin
homeostasis and the course of retinal degeneration in ...

## Key facts

- **NIH application ID:** 10917253
- **Project number:** 5R01EY020866-14
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** HYUNG D RYOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,163
- **Award type:** 5
- **Project period:** 2010-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917253

## Citation

> US National Institutes of Health, RePORTER application 10917253, Unfolded Protein Response in Drosophila models of Retinitis Pigmentosa (5R01EY020866-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10917253. Licensed CC0.

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