Author: Gulpreet KaurPublisher:
ISBN:
Category :
Languages : en
Pages : 87
Book Description
The retinal pigment epithelium (RPE) performs many functions that are indispensable for vision, such as recycling vitamin A for the visual cycle, and participating in the daily renewal of photoreceptors. Over time, vitamin A metabolites, called lipofuscin, accumulate within RPE lysosomes and are thought to compromise RPE and photoreceptor health and promote inflammation. The RPE is also an initial site of insult in blinding diseases such as age-related macular degeneration. Accumulation of lipofuscin is a feature of inherited macular degenerations and could also contribute to age-related macular degeneration (AMD); however, the mechanisms behind this are still under study. We have previously established that RPE with vitamin A metabolites have increased ceramide and defects in autophagic and endo-lysosomal pathways. In this study, we have investigated two consequences of ceramide accumulation: 1) increased biogenesis of early endosomes, due to ceramide-induced negative curvature and inward budding; and 2) altered organelle traffic due to ceramide-induced accumulation of acetylated microtubules. First, we have identified the mechanism by which ceramide accumulation in RPE with vitamin A metabolites leads to enlarged early endosomes. These swollen endosomes internalize and cleave the complement protein, C3, into its active component, C3a. The acid sphingomyelinase inhibitor, desipramine reduces ceramide levels in RPE with vitamin A metabolites, corrects early endosome defects, and prevents complement activation. Second, we have previously noted that RPE with vitamin A metabolites have defective autophagosome trafficking and autophagic flux. In this study, we investigated the role of histone deacetylase 6 (HDAC6), a tubulin deacetylator, in autophagy. We established that HDAC6 inhibition results in accumulation of acetylated microtubules and reduced autophagic flux and trafficking. It remains to be determined if acetylated microtubule accumulation in RPE with vitamin A metabolites is dependent on HDAC6 activity. Our approach is to study healthy and stressed RPE at a cellular and molecular level, using techniques such as high-speed live imaging of polarized primary RPE cultures and mouse models of inherited macular degeneration, such as the Abca4-/- model of Stargardt disease. Our studies have investigated the role of organelle morphology and dynamics in maintenance of RPE health.