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Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin
- Source :
- JCI Insight, Vol 6, Iss 5 (2021), JCI Insight
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Cell biology
genetic structures
Mutant
Ocular hypertension
Glaucoma
CHOP
03 medical and health sciences
0302 clinical medicine
Trabecular Meshwork
Autophagy
medicine
Animals
Humans
Eye Proteins
Cells, Cultured
Myocilin
Glycoproteins
Mice, Knockout
Chemistry
General Medicine
Cell stress
medicine.disease
eye diseases
Mice, Inbred C57BL
Cytoskeletal Proteins
Ophthalmology
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
CCAAT-Enhancer-Binding Proteins
Unfolded protein response
Medicine
Ocular Hypertension
sense organs
Trabecular meshwork
Glaucoma, Open-Angle
Research Article
Protein misfolding
Subjects
Details
- ISSN :
- 23793708
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....9fe5438e3143db2e3a977ffd72a9d143