Nilsa La Cunza

UC San Francisco

“The Apolipoprotein E Enigma in Age-Related Macular Degeneration”

Common pathogenic mechanisms underlying many neurodegenerative disorders include cholesterol accumulation, mitochondrial damage, and the accumulation of extracellular protein aggregates. These dysfunctions are also implicated in AMD, the leading cause of permanent vision loss in the elderly. Clinically, RPE abnormalities and deposition of lipid-protein aggregates called drusen above and beneath the RPE are indicators of progressive vision loss. How drusen form and how they contribute to disease are not well understood. ApoE is a cholesterol transporter and only humans express ApoE allelic variants, which show reversed risk associations between AMD and Alzheimer’s disease. I sought to investigate how ApoE isoforms regulate cholesterol transport and mitochondrial health and determine how this could contribute to drusen biogenesis. Using high-speed live imaging and bioinformatics analyses, I identified a novel mechanism that links RPE mitochondrial injury and cholesterol accumulation with drusen biogenesis.

ABSTRACT

Our research targets the cellular mechanisms behind vision loss in age-related macular degeneration (AMD), impacting over 30 million people worldwide by destroying central, high-resolution vision. We study the retinal pigment epithelium (RPE), which nourishes and supports the light-sensing photoreceptors in the retina. Using cutting-edge live imaging technology, I have discovered a novel mechanism involving liquid-liquid phase separation that links mitochondrial fragmentation in the RPE with the formation of lipid-protein aggregates called drusen, which are a hallmark of AMD.
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