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Sub-region-Specific Optic Nerve Head Glial Activation in Glaucoma

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Abstract

Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage–specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type–specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.

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Data Availability

The datasets generated and/or analyzed during the current study are available the NCBI’s Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo; accession number: GSE110019).

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Acknowledgments

The authors would like to thank Akihiro Ikeda, Robert Nickells, Dale Bjorling, and Colin Dewey for their advice on the conduct of these studies; Satoshi Kinoshita for preparation of cryosections; Ben August for preparation of semi-thin optic nerve sections; Carol A. Rasmussen and Elizabeth A. Hennes-Beean for technical support and acquisition of OCT images and electrophysiology data, respectively; Youngwoo Park and Jaesang Ahn for assistance with tissue dissection, OCT analysis, and axon counting; UW-Madison’s Biotechnology Center for library preparation, sequencing, and the support of bioinformatics analyses; and the student trainees and laboratory assistants in the McLellan lab who assisted with animal procedures and collation of data.

Funding

The studies were supported in part by NIH Grants K08 EY018609 and R01 EY027396 (GJM); S10 OD018221, P30 EY0016665, and a CTSA award from UW-Madison’s Institute for Clinical and Translational Research through NCATS grant UL1TR000427 (GJM); a National Glaucoma Research Grant from the BrightFocus Foundation (GJM); a Grant-in-Aid Award from Fight For Sight (GJM); the University of Wisconsin–Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation (GJM); and an unrestricted grant to the University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness. Additional support was provided by the Center for Integrated Animal Genomics, Iowa State University (NME and GJM); a Battelle General Platform and Infrastructure Award (NME); and a JASSO scholarship (awarded to KO). Tissue sectioning was performed by the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of The Director- NIH (S10OD023526).

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Authors and Affiliations

  1. Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI, USA

    Kazuya Oikawa, Kevin C. Snyder & Gillian J. McLellan

  2. Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 1300 University Avenue, Madison, WI, 53706, USA

    Kazuya Oikawa, James N. Ver Hoeve, Julie A. Kiland & Gillian J. McLellan

  3. McPherson Eye Research Institute, Madison, WI, USA

    Kazuya Oikawa, James N. Ver Hoeve, Leandro B. C. Teixeira, Kevin C. Snyder & Gillian J. McLellan

  4. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA

    Leandro B. C. Teixeira

  5. Department of Animal Science, Iowa State University, Ames, IA, USA

    N. Matthew Ellinwood

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Contributions

KO and GJM conceived and designed the experiments and overall project; NME provided LTBP2 mutant animals and other resources; GJM acquired optical coherence tomography images. GJM and JAK coordinated, supervised and/or conducted clinical testing. Project specific, custom analysis tools for electrophysiology data were developed and provided by JNV who supervised analyses by KO and KCS. LBCT developed tools for and performed optic nerve axon counts. KO conducted all other experiments. GJM and KO reviewed all data and conducted statistical analyses. All bioinformatic analyses of RNA-seq data were conducted by KO with support from UW-Madison’s Bioinformatics Resource Center. KO and GJM wrote the manuscript with contributions from all co-authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Gillian J. McLellan.

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All animal procedures were conducted in accordance with the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research, the NIH Guide for the Care and Use of Laboratory Animals, and in compliance with protocols approved by the University of Wisconsin-Madison’s IACUC.

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The authors declare that they have no competing interests.

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Oikawa, K., Ver Hoeve, J.N., Teixeira, L.B.C. et al. Sub-region-Specific Optic Nerve Head Glial Activation in Glaucoma. Mol Neurobiol 57, 2620–2638 (2020). https://doi.org/10.1007/s12035-020-01910-9

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