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Heterozygous Meg2 Ablation Causes Intraocular Pressure Elevation and Progressive Glaucomatous Neurodegeneration

  • Jacqueline Reinhard
  • Susanne Wiemann
  • Stephanie C. Joachim
  • Marina Palmhof
  • Julia Woestmann
  • Bernd Denecke
  • Yingchun Wang
  • Gregory P. Downey
  • Andreas Faissner
Article

Abstract

Glaucomatous neurodegeneration represents one of the major causes of irreversible blindness worldwide. Yet, the detailed molecular mechanisms that initiate optic nerve damage and retinal ganglion cell (RGC) loss are not fully understood. Members of the protein tyrosine phosphatase (PTP) superfamily are key players in numerous neurodegenerative diseases. In order to investigate the potential functional relevance of the PTP megakaryocyte 2 (Meg2) in retinal neurodegeneration, we analyzed Meg2 knockout (KO) and heterozygous (HET)—synonym protein-tyrosine phosphatase non-receptor type 9 (Ptpn9)—mice. Interestingly, via global microarray and quantitative real-time PCR (RT-qPCR) analyses of Meg2 KO and HET retinae, we observed a dysregulation of several candidate genes that are highly associated with retinal degeneration and intraocular pressure (IOP) elevation, the main risk factor for glaucoma. Subsequent IOP measurements in Meg2 HET mice verified progressive age-dependent IOP elevation. Ultrastructural analyses and immunohistochemistry showed severe optic nerve degeneration accompanied by a dramatic loss of RGCs. Additionally, HET mice displayed reactive micro-/macrogliosis and early activation of the classical complement cascade with pronounced deposition of the membrane attack complex (MAC) in the retina and optic nerve. When treated with latanoprost, significant IOP lowering prevented RGC loss and microglial invasion in HET mice. Finally, electroretinogram (ERG) recordings revealed reduced a- and b-wave amplitudes, indicating impaired retinal functionality in Meg2 HET mice. Collectively, our findings indicate that the heterozygous loss of Meg2 in mice is sufficient to cause IOP elevation and glaucomatous neurodegeneration. Thus, Meg2 HET mice may serve as a novel animal model to study the pathomechanism involved in the onset and progression of glaucoma.

Keywords

Glaucoma Intraocular pressure elevation Mouse model Neurodegeneration Protein tyrosine phosphatase Meg2 Retina 

Notes

Acknowledgements

The authors thank Zülal Caka, Stephanie Chun, Anja Coenen, Holger Schlierenkamp, and Marion Voelzkow for their excellent technical assistance.

Funding Information

This research was supported by the German Research Foundation (DFG: SFB 509 TPA10; FA 159/14-1). J. R. was supported by the Research School, Ruhr-University Bochum (DFG: GSC 98/1). S. W. was supported by the Konrad-Adenauer Foundation (200520593).

Compliance with Ethical Standards

Ethical Approval

All animal experiments were conducted in compliance with the “Association for Research and Vision and Ophthalmology” statement for the use of animals in ophthalmic and vision research and were approved by the ethics committee for animal experiments by the state North-Rhine Westphalia, Germany. The study was supervised by the animal welfare commissioner of the Ruhr-University Bochum. All efforts were made to reduce the number of animals in the experiments.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1376_MOESM1_ESM.pdf (2.2 mb)
ESM 1 (PDF 2.20 mb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jacqueline Reinhard
    • 1
  • Susanne Wiemann
    • 1
  • Stephanie C. Joachim
    • 2
  • Marina Palmhof
    • 2
  • Julia Woestmann
    • 1
  • Bernd Denecke
    • 3
  • Yingchun Wang
    • 4
  • Gregory P. Downey
    • 5
    • 6
  • Andreas Faissner
    • 1
  1. 1.Department of Cell Morphology and Molecular Neurobiology, NDEF 05/594, Faculty of Biology and BiotechnologyRuhr-University BochumBochumGermany
  2. 2.Experimental Eye Research Institute, University Eye HospitalRuhr-University BochumBochumGermany
  3. 3.Interdisciplinary Centre for Clinical ResearchRWTH Aachen UniversityAachenGermany
  4. 4.Division of Respirology, Department of MedicineUniversity of Toronto and Toronto General Hospital Research Institute of the University Health NetworkTorontoCanada
  5. 5.Division of Pulmonary Sciences and Critical Care Medicine, Departments of Medicine and Immunology and MicrobiologyUniversity of ColoradoAuroraUSA
  6. 6.Division of Pulmonary, Critical Care and Sleep Medicine, Departments of Medicine, Pediatrics and Biomedical ResearchNational Jewish HealthDenverUSA

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