The Role of Mitochondrial Dysfunction in Age-Related Macular Degeneration

The aim of this project is to clarify the effect of a risk-related gene on mitochondrial dysfunction and fat processing in age-related macular degeneration.

A protein strongly associated with age-related macular degeneration may lead to increased disease risk through dysfunction of the mitochondria, which package usable energy for the cell. The protein called age-related maculopathy susceptibility 2 or ARMS2, occurs in different forms, some of them especially linked to risk for the disease. The protein effects that underlie that risk are unclear, however. Navdeep Gogna, PhD, and her colleagues plan to address this question using lab models of age-related macular degeneration that bear human-like characteristics of the disease. Early results already implicate the involvement of the mitochondria and how cells process fats, which are important for retinal health and function.

In addition to using their innovative lab model of the disease, Dr. Gogna and her coworkers will apply sophisticated molecular profiling tools to track how cells process fats and whether specific features related to ARMS2 activity affect this processing. Their work will yield new understanding as the first investigation of how a specific form of ARMS2 influences mitochondrial function and fat processing. Uncovering how ARMS2 leads to vulnerability to age-related macular degeneration could in turn lead to new treatment targets for the disease.

Our humanized transgenic ARMS2 mouse model with an endogenous promoter inserted upstream of Htra1 that expresses ARMS2 in the same temporal and spatial pattern observed in humans is novel. While mitochondrial dynamics and lipid metabolism are known to be important for RPE health and implicated in AMD, they have not been studied in the context of the ARMS2A69S risk variant. Further, our study uniquely employs both conventional techniques and cutting-edge approaches to identify the mechanisms that lead to disease-associated changes in ARMS2A69S mice.

Benefits to the research field – A new humanized ARMS2 mouse model for AMD with insights about the sequential changes in mitochondrial and lipid-related mechanisms that predispose the A69S variant to AMD risk. These mice will be made available for further dissection and validation of common mechanisms related to AMD risk. Benefits to the general public – These mechanisms when leveraged for testing therapeutic targets, will provide better curative or preventive treatments for AMD.