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Resource and Technical AdvanceIn-Press PreviewGeneticsNeuroscienceOphthalmology Open Access | 10.1172/jci.insight.188710

Impaired axonal transport contributes to neurodegeneration in a Cre-inducible mouse model of myocilin-associated glaucoma

Balasankara Reddy Kaipa,1 Ramesh Kasetti,2 Yogapriya Sundaresan,1 Linya Li,1 Sam Yacoub,2 J. Cameron Millar,2 William Cho,1 Dorota Skowronska-Krawczyk,1 Prabhavathi Maddineni,3 Krzysztof Palczewski,1 and Gulab S. Zode1

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Kaipa, B. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Kasetti, R. in: JCI | PubMed | Google Scholar |

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Sundaresan, Y. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Li, L. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Yacoub, S. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Millar, J. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Cho, W. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Skowronska-Krawczyk, D. in: JCI | PubMed | Google Scholar |

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Maddineni, P. in: JCI | PubMed | Google Scholar

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Palczewski, K. in: JCI | PubMed | Google Scholar |

1Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America

2Department of Pharmacology and Neuroscience, North Texas Eye Research Insti, University of North Texas Health Science Center at Fort Worth, Fort Worth, United States of America

3Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, United States of America

Find articles by Zode, G. in: JCI | PubMed | Google Scholar

Published January 21, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.188710.
Copyright © 2025, Kaipa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 21, 2025 - Version history
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Abstract

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking. We report the development and characterization of a novel Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing the outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant loss of retinal ganglion cells (RGCs) and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437H mice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.

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