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LysoSENS at Arizona State University

Degradation of A2E

Principal Investigators: Bruce Rittmann, Claudia Schmidt-Dannert, Janet Sparrow

Research Team: John Schloendorn, Lorenzo Albanello, Keith Causey, Brian Cook, Mark Hamalainen, David Jackemeyer, Lijing Jiang, Kent Kemmish, Daniel Kimbel, Horacio Ramirez, Justin Rebo, Jonathan Sankman, Nason Schooler, Lindsey Sherman, Lauri Tontson, Tim Webb

Various forms of macular degeneration may be caused or exacerbated by the accumulation of A2E, a toxic bisretinoid that arises in a non-enzymatic side-reaction of the visual cycle. A2E is resistant to degradation, and accumulates in the lysosomes of retinal pigment epithelial cells throughout the lifespan.
In age-related macular degeneration, A2E levels are thought to reach a toxic threshold, causing lysosomal failure and degeneration of the RPE - and then the photoreceptors that depend on it. In Stargardt’s disease, A2E accumulation is congenitally accelerated, resulting in early-onset macular degeneration, probably due to the same mechanism.  Approximately 10% of patients aged 66 to 74 have symptoms of macular degeneration, and the prevalence increases to 30% for patients ages 75 to 85.
A2E was targeted for therapeutic intervention with lysosomal degrading enzymes in 2008.  SENS researchers appealed to supporters across the world to provide soil samples to facilitate screening for microbial enzymes which could degrade this compound.  This helped to contribute to the identification of numerous A2E-degrading enzymes.  Amongst the A2E peroxidases tested (from this and other sources), five were marked as candidate enzymes. These enzymes were modified with glycosylation patterns which would allow them to be recognized by human RPE cells and subsequently localized to the A2E-loaded lysosomes. This modification should allow for the post-translational addition of mannose (an identifying carbohydrate) which is detected by mannose receptors which induce lysosomal targeted endocytosis.
Our work at Arizona State University concluded in 2009, upon the creation of SRF's intramural research program.
SRF would like to extend a special thanks to John Schloendorn and Bruce Rittman for their work in bringing in so many individuals who were just getting started in the research arena during this formative time, many of whom have gone on to become key players in ongoing projects.