# Endosome regulated retinal homeostasis and disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $517,936

## Abstract

Project Summary/Abstract
Loss of function and viability of rod photoreceptors is central to the etiology of retinitis pigmentosa
(RP) which affects 1 in ~4,000. Our lab has a long-term interest in understanding the endosome's role
in membrane trafficking of photoreceptors and much has been learned about the outer segment
protein targeting. In contrast, we know very little about how the mistrafficked proteins are degraded,
and the consequence(s) of the generation of non-degradable wastes. Emerging studies showed the
endo-lysosomal system is a genetic hot spot for several neurological diseases such as Alzheimer's
and Parkinson's, whose pathology is contributed by both the primary neuronal lesions and sustained
microglial inflammation. During the past grant period, we generated a mouse line with rod-specific
deletion of VPS35. The early endosomal protein VPS35 is the hub that centrally controls several
interconnected trafficking pathways. VPS35 has been genetically linked to Alzheimer's and
Parkinson’s. Our results showed that in these mutant mice several outer segment proteins were
mislocalized and underwent proteolytic degradation. Strikingly, VPS35 deficient rod terminals
accumulated massive lipid-membrane wastes, which were engulfed by the surrounding microglia,
which then migrated away to the subretinal space. The latter expressed the molecular signatures of
disease-associated microglia identified in Alzheimer's mouse models. The level of sphingolipid, which
has been connected to synaptic membrane integrity and neural inflammation, was also abnormally
elevated in mutant mice. The overarching goal here is to test a central hypothesis that the engulfment
of the rod-derived sphingolipid-rich wastes activates microglia, leading to several functional deficits
(e.g., phagocytosis, clearance) and inflammation. We will mechanistically investigate the pathological
contribution by sphingolipids (Aim1) and microglia (Aim2) using interdisciplinary and state-of-the-art
techniques (e.g., lipidomics, transcriptomes, 3D electron microscopy, multi-antigen flow cytometry)
both in vivo and in vitro. We will also address whether inhibiting any of these pathways can offset the
sustained microglial inflammation, and in turn, ameliorate retinal pathology. The proposed studies will
provide keen insights into the fundamental understanding of the retina homeostasis harnessed by the
photoreceptor-microglia crosstalk. They have a high potential to lead to new strategies for treating RP
and potentially other neurological diseases with overlapping etiologies.

## Key facts

- **NIH application ID:** 10931526
- **Project number:** 5R01EY029428-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** CHING-HWA SUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $517,936
- **Award type:** 5
- **Project period:** 2018-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931526

## Citation

> US National Institutes of Health, RePORTER application 10931526, Endosome regulated retinal homeostasis and disease (5R01EY029428-06). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10931526. Licensed CC0.

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