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

Abstract

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.

Keywords: myocilin; neurodegenerative disease; ocular hypertension; primary open angle glaucoma.

Figure 1

Signaling pathways of the UPR in response to ER-stress. The UPR is regulated through signaling cascades from three sensor proteins: IRE1, ATF6 and PERK. During non-stressed conditions, BiP (red pie) is bound to the three sensors to maintain their inactive state. When misfolded proteins accumulate in the lumen of the ER, BiP dissociates from the sensors and binds to unfolded and misfolded proteins. This results in activation of the IRE1, ATF6 and PERK signaling cascades. Dissociation of BiP from IRE1 results in its dimerization which activates its kinase and RNAse activities to promote splicing of Xbp1 mRNA resulting in a frame shift of the Xbp1 gene. Translation of spliced Xbp1 produces an active transcription factor which subsequently induces the translation of ER chaperones and genes involved in ER-associated protein degradation (ERAD). ATF6 is a basic leucine-zipper (bZIP) containing transcription factor. During ER-stress, BiP dissociates and ATF6 is translocated to the Golgi apparatus where it is cleaved by two proteases (serine protease site-1 protease (S1P) and serine protease site-2 protease (S2P). The cytosolic fragment of ATF6 migrates to the nucleus and activates transcription of UPR-responsive genes such as chaperones and CHOP, through promoter binding at their ER-stress response element binding sites. PERK is a serine/threonine protein kinase activated by ER-stress through dimerization and autophosphorylation upon dissociation of BiP. Activated PERK phosphorylates eIF2α, resulting in the inhibition of global translation. However, ATF4 is translated because it contains multiple 5’ open reading frames. ATF4 induces CHOP (a proapoptotic transcription factor) which activates the apoptosis pathway.

Figure 2

Consequences of overexpression of human myocilin in the Drosophila eye. (A) shows a normal Drosophila eye. (B) illustrates the fluid extrusion phenotype that results from expression of human myocilin. (C) shows a histological section through a normal Drosophila eye with a regular array of ommatidia. In transgenic flies that express myocilin this regular array of ommatidia is disrupted and they appear distended, as shown in (D). (E) shows a region where a dimple appears (between arrows) underneath which ommatidia appear to have regained their normal shape. This dimpled region has likely undergone recent fluid extrusion resulting in temporary relieve of hydrostatic pressure in the underlying tissue.