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Ryan Thummel, Xixia Luo, Alan Dombkowski, James Granneman; Aberrant Protein Trafficking Underlies Vision Defects in Syndromic Albinism. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1807.
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Clinical syndromic albinism is associated with other systemic diseases in addition to oculocutaneous albinism (OCA). Many of these syndromes exhibit defects in protein sorting and trafficking in lysosomes and lysosome-related organelles, such as melanosomes. We recently identified a zebrafish mutant for vps11, one of the HOPS/C-Vps class of protein-sorting genes. Based primarily on work done in yeast, Vps11 is hypothesized to function in endosome-to-lysosome and endosome-to-melanosome protein trafficking, resulting in both OCA and systemic defects related to lysosomal abnormalities. The purpose of this study is to determine how loss of Vps11 leads to vision defects in a zebrafish model of syndromic albinism.
Zebrafish vps11 mutants were analyzed for pigmentation defects, RPE degeneration, and retinal pathology by histology, immunohistochemistry, cell death analysis, and transmission electron microscropy. Microarray analysis of mutant and wild-type eyes was performed at 3, 5, and 7 day post-fertilization (dpf). Autophagy inhibition was performed in vivo using known pharmacological inhibitors.
We showed that loss of Vps11 results in both OCA and systemic defects, such as pericardial edema, hepatomegaly, and premature death. Specifically, vps11 mutant zebrafish exhibited reduced pigmentation in body melanophore and retinal pigmented epithelium (RPE) due to a disruption in melanosome maturation. Vps11 was not required for photoreceptors or the RPE to form normally; however, vps11 mutants exhibited subsequent degeneration of the RPE and photoreceptors. Notably, we show independent cell death mechanisms in the retina and RPE following loss of Vps11 function. Retinal cell death precedes RPE death in vps11 mutant zebrafish and occurs via apoptosis. In contrast, microarray and pharmacological data indicate that RPE loss is autophagy-dependent and not classical caspase-dependent apoptosis.
Loss of Vps11 leads to syndromic albinism, suggesting that aberrant protein trafficking underlies vision defects associated with these syndromes. Interestingly, our data suggest that Vps11 performs different cell autonomous roles in the retina and RPE. As a means of determining the underlying cause of these phenotypes, we are currently testing whether mutant Vps11 can interact with the other members of the C-Vps complex, with lysosomes, or with autophagosomes.
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