TitleOverexpression of myocilin in the Drosophila eye activates the unfolded protein response: implications for glaucoma.
Publication TypeJournal Article
Year of Publication2009
AuthorsCarbone, MAnna, Ayroles, JF, Yamamoto, A, Morozova, TV, West, SA, Magwire, MM, Mackay, TFC, Anholt, RRH
JournalPLoS One
Volume4
Issue1
Paginatione4216
Date Published2009
KeywordsAnimals, Animals, Genetically Modified, Biochemical Processes, Cytoskeletal Proteins, Drosophila, Eye, Eye Proteins, Glaucoma, Glycoproteins, Humans, Intraocular Pressure, Peptide Hydrolases, Proteins, Ubiquitination
Abstract

BACKGROUND: Glaucoma is the world's second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2-4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism.

METHODOLOGY / PRINCIPAL FINDINGS: We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. CONCLUSIONS / SIGNIFICANCE: Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOC-associated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma.

Alternate JournalPLoS ONE