Autophagic dysregulation in glaucomatous trabecular meshwork cells

Kristine Porter, Joshua Hirt, W. Daniel Stamer, Paloma B. Liton

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)379-385
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number3
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Autophagy
  • Glaucoma
  • Lysosomal proteolysis
  • MTOR
  • Oxidative stress
  • Trabecular meshwork

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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