title: Autophagic dysregulation in glaucomatous trabecular meshwork cells.
abstract: Primary open angle glaucoma (POAG) is a degenerative disease commonly associated with aging and elevated intraocular pressure (IOP). Higher resistance to aqueous humor (AH) outflow through the trabecular meshwork (TM) generates the elevated IOP in POAG; unfortunately the underlying molecular mechanisms responsible for elevated resistance are unknown. It is widely accepted, however, that differences between normal and POAG TM tissues are presumably a consequence of cellular dysfunction. Here, we investigated the autophagic function and response to chronic oxidative stress in TM cells isolated from glaucomatous and age-matched donor eyes. Glaucomatous TM cells showed elevated senescence-associated-beta-galactosidase (SA-β-Gal) and cellular lipofuscin, together with decreased steady-state levels of LC3B-II, decreased levels of pRPS6K-T389 and reduced proteolysis of long-live proteins. Moreover, the glaucomatous cultures failed to activate autophagy when exposed to hyperoxic conditions. These results strongly suggest mTOR-dependent dysregulation of the autophagic pathway in cells isolated from the glaucomatous TM. Such dysregulated autophagic capacity can have a detrimental impact in outflow pathway tissue, i.e. mechanotransduction, and thus represent an important factor contributing to the progression of the disease.
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Porter
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hirt
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
authors.affiliation: Duke University, Department of Ophthalmology, Durham, NC, USA. Electronic address: paloma.liton@dm.duke.edu.
authors.forename: Paloma B
authors.initials: PB
authors.lastname: Liton
mesh_terms: D001343:Autophagy; D002478:Cells, Cultured; D005136:Eye Proteins / Q000378:metabolism*; D005902:Glaucoma, Open-Angle / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007429:Intraocular Pressure; D018384:Oxidative Stress; D059748:Proteolysis; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology
chemical_list: D005136:Eye Proteins
keywords: Autophagy; Glaucoma; Lysosomal proteolysis; Oxidative stress; Trabecular meshwork; mTOR