M2-Isoform of Pyruvate Kinase is a Biomarker for Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the major cause of vision loss in the Western world, affecting approximately 15% of the elderly. The central portion of the retina, directly opposite the lens, is called the macula. It is rich in cones, the cells that enable us to see fine detail and color. At the center of the macula is a very small area called the fovea. Cones are most concentrated in the fovea. Despite its small size relative to the rest of the retina, the fovea is very important for our ability to see fine detail and color. In macular degeneration, the light-sensing cells of the macula mysteriously malfunction and may cease to work over time. Retinal pigment epithelial cells (RPE) of the retina provide nourishment to photoreceptor cells for normal visual functions. Recent studies show that in AMD patients’ retinas and aged mouse tissues, expression of two enzymes, pyruvate kinase M2 and Aldolase C, is increased in the RPE and is decreased in the photoreceptor cells. In normal retina, the expression of these two enzymes is low in RPE and high in the photoreceptors. Furthermore, AMD patients’ sera show anti-retinal antibodies towards PKM2 and aldolase, suggesting that these two enzymes could be used as biomarkers for AMD. In this grant proposal, we propose to study the mechanism of these two enzyme alterations and also reprogram their expression to reduce the AMD phenotype. Prolonging the life of foveal cones for even one decade would have a huge beneficial effect on usable vision in an aging population.
The principal thrust of my current research is to redefine our understanding of neurodegeneration by illuminating parallels between cancer metabolism and photoreceptor degenerative diseases. Light-sensing photoreceptor cells in the retina are terminally differentiated, thus once they are lost, and they cannot regenerate, making the development of potential therapies infinitely more challenging. As a result, currently available treatments can only delay vision loss; they cannot prevent it.
It has been shown that there exists a delicate metabolic ecosystem exists between RPE and Retina, changes in which can contribute to the rise of diseases. In Age-related macular degeneration (AMD), it has been demonstrated that pyruvate kinase M2 (PKM2) isoform and aldolase C (ALDOC) isoform, metabolic reprogrammers, may play a pivotal role in this ecosystem, and thusly a major role in AMD. Our first aim is to study what role PKM2 plays in the RPE, which may shed light on some mechanisms that induce AMD. This would guide us in designing effective therapies for these blinding diseases by translating our findings into the treatment of AMD.
In Aim 2, we will study what role ALDOC in photoreceptors, which would also help guide us in designing effective therapies for these blinding diseases.