I am interested in understanding the molecular mechanisms underlying neurodegenerative diseases and I believe forward genetics approaches will help us unravel the mechanisms. I have therefore participated in a large scale screen on the Drosophila X chromosome to isolate mutants with neurodegenerative phenotypes and to study the function of the responsible genes. I am now studying a gene called Crag, which was previously implicated to regulate the trafficking of basement membrane proteins in the Drosophila oocytes (Denef et al., 2008). Mutations in Crag lead to a light-induced retinal degeneration and Crag mutant
photoreceptor (PR) cells show a normal light response in electroretinogram recordings (ERGs) in newly eclosed animals, indicating that the cells develop properly. Aging the flies for a three week period in a 12-hour on/off light cycle leads to severely reduced light responses. Electron microscopy (EM) of retina cross sections shows that PR cell organelles gradually deteriorate in Crag mutant cells. However, when kept in dark, these mutant cells do not degenerate based on ERG and TEM data. I have also discovered that Crag is required for light adaptation by regulating light induced translocation of Arrestin 2, a major negative regulator of the phototransduction pathway. With light exposure, defects in light adaptation seem to cause excessive photo responses, which finally lead to cellular stress and cell death.
Based on sequence homology, I propose that Crag may be a GDP/GTP Exchange Factor (GEF) for Rab proteins, and may therefore regulate protein trafficking in photoreceptor cells. I am currently testing these hypotheses.
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