A molecular mechanism for glaucoma: endoplasmic reticulum stress and the unfolded protein response

• Accumulation of protein aggregates may overwhelm the UPR and result in ER stress.
• Impairment of the UPR which results in ER stress may be a common cause for POAG.
• Aspects of POAG resemble other neurodegenerative protein aggregation diseases.

Primary open angle glaucoma (POAG) is a common late-onset neurodegenerative disease. Ocular hypertension represents a major risk factor, but POAG etiology remains poorly understood. Some cases of early-onset congenital glaucoma and adult POAG are linked to mutations in myocilin, a secreted protein of poorly defined function. Transgenic overexpression of myocilin in Drosophila and experiments in mice and human populations implicate the unfolded protein response (UPR) in the pathogenesis of glaucoma. We postulate that compromised ability of the UPR to eliminate misfolded mutant or damaged proteins, including myocilin, causes endoplasmic reticulum stress, resulting in functional impairment of trabecular meshwork cells that regulate intraocular pressure. This mechanism of POAG is reminiscent of other age-dependent neurodegenerative diseases that involve accumulation of protein aggregates.