AI Article Synopsis

  • Elevated intraocular pressure (IOP) from trabecular meshwork damage is linked to primary open-angle glaucoma (POAG), primarily caused by myocilin mutations.
  • Mutant myocilin causes chronic endoplasmic reticulum (ER) stress and increases IOP, but its link to trabecular meshwork dysfunction was unclear until now.
  • The study found that enhancing autophagy can help clear mutant myocilin, reduce IOP, and offer new treatment options for myocilin-related POAG.

Article Abstract

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) damage is associated with primary open-angle glaucoma (POAG). Myocilin mutations resulting in elevated IOP are the most common genetic causes of POAG. We have previously shown that mutant myocilin accumulates in the ER and induces chronic ER stress, leading to TM damage and IOP elevation. However, it is not understood how chronic ER stress leads to TM dysfunction and loss. Here, we report that mutant myocilin activated autophagy but was functionally impaired in cultured human TM cells and in a mouse model of myocilin-associated POAG (Tg-MYOCY437H). Genetic and pharmacological inhibition of autophagy worsened mutant myocilin accumulation and exacerbated IOP elevation in Tg-MYOCY437H mice. Remarkably, impaired autophagy was associated with chronic ER stress-induced transcriptional factor CHOP. Deletion of CHOP corrected impaired autophagy, enhanced recognition and degradation of mutant myocilin by autophagy, and reduced glaucoma in Tg-MYOCY437H mice. Stimulating autophagic flux via tat-beclin 1 peptide or torin 2 promoted autophagic degradation of mutant myocilin and reduced elevated IOP in Tg-MYOCY437H mice. Our study provides an alternate treatment strategy for myocilin-associated POAG by correcting impaired autophagy in the TM.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021112PMC
http://dx.doi.org/10.1172/jci.insight.143359DOI Listing

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