The physiological and pathophysiological roles of the autophagy lysosomal system in the conventional aqueous humor outflow pathway: More than cellular clean up |
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| Affiliation: | 1. Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;2. Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA;3. Department of Medicine, Duke University Medical Center, Durham, NC, USA;4. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA;5. Duke Molecular Physiology Institute, Durham, NC, USA;1. Retina and Optic Nerve Research Laboratory, Dalhousie University, Halifax, Nova Scotia, Canada;2. Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada;3. Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada;4. Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;1. Ocular Oncology Service, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029, HUS, Helsinki, Finland;2. Comprehensive Cancer Center, Department of Oncology, Helsinki University Hospital and University of Helsinki, Paciuksenkatu 3, PL 180, FI-00029, HUS, Helsinki, Finland;3. Department of Medical Oncology, Institut Curie, 26, rue d''Ulm, 75005, Paris, France;4. Section of Ocular Oncology, Emory Eye Center, 1365 Clifton Road B, Atlanta, GA, 30322, USA;1. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;2. Department of Ophthalmology, Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;3. Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC, USA;1. Singapore Eye Research Institution, Singapore National Eye Centre, Singapore;2. Duke-NUS Medical School, National University of Singapore, Singapore;3. Northwestern University, Illinois, USA;4. Hyogo College of Medicine, Nishinomiya, Japan;5. Aravind Eye Hospital, Madurai, India;6. NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, United Kingdom;1. Department of Psychology, Columbia University, New York, NY, 10027, USA;2. Bernard and Shirlee Brown Glaucoma Research Laboratory, Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY, USA, 10032;3. Department of Biomedical Engineering, Columbia University, New York, 10027, NY, USA;4. Albert Einstein College of Medicine, New York, NY, 10461, USA;5. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel |
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| Abstract: | During the last few years, the autophagy lysosomal system is emerging as a central cellular pathway with roles in survival, acting as a housekeeper and stress response mechanism. Studies by our and other labs suggest that autophagy might play an essential role in maintaining aqueous humor outflow homeostasis, and that malfunction of autophagy in outflow pathway cells might predispose to ocular hypertension and glaucoma pathogenesis. In this review, we will collect the current knowledge and discuss the molecular mechanisms by which autophagy does or might regulate normal outflow pathway tissue function, and its response to different types of stressors (oxidative stress and mechanical stress). We will also discuss novel roles of autophagy and lysosomal enzymes in modulation of TGFβ signaling and ECM remodeling, and the link between dysregulated autophagy and cellular senescence. We will examine what we have learnt, using pre-clinical animal models about how dysregulated autophagy can contribute to disease and apply that to the current status of autophagy in human glaucoma. Finally, we will consider and discuss the challenges and the potential of autophagy as a therapeutic target for the treatment of ocular hypertension and glaucoma. |
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| Keywords: | Autophagy Trabecular meshwork Glaucoma Mechanical stress Primary cilia Cathepsins Lysosomes ECM |
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