Journal article
Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin
JCI insight, Vol.6(5), e143359
03/08/2021
DOI: 10.1172/jci.insight.143359
PMCID: PMC8021112
PMID: 33539326
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-MYOC
Y437H
). Genetic and pharmacological inhibition of autophagy worsened mutant myocilin accumulation and exacerbated IOP elevation in
Tg-MYOC
Y437H
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-MYOC
Y437H
mice. Stimulating autophagic flux via tat-beclin 1 peptide or torin 2 promoted autophagic degradation of mutant myocilin and reduced elevated IOP in
Tg-MYOC
Y437H
mice. Our study provides an alternate treatment strategy for myocilin-associated POAG by correcting impaired autophagy in the TM.
Details
- Title: Subtitle
- Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin
- Creators
- Ramesh B Kasetti - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USAPrabhavathi Maddineni - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USACharles Kiehlbauch - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USAShruti Patil - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USACharles C Searby - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USABeth Levine - Center for Autophagy Research, Department of Internal MedicineVal C Sheffield - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAGulab S Zode - Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.6(5), e143359
- DOI
- 10.1172/jci.insight.143359
- PMID
- 33539326
- PMCID
- PMC8021112
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- EY026177,EY028616,EY030366 / Natiional Eye Institute
- Language
- English
- Date published
- 03/08/2021
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070955202771
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