Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Nitin Chitranshi; Yogita Dheer; Mehdi Mirzaei; Yunqi Wu; Ghasem H Salekdeh; Mojdeh Abbasi; Veer Gupta; Roshana Vander Wall; Yuyi You; Stuart L Graham; Vivek Gupta

doi:10.1016/j.ymthe.2018.09.019

Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Mol Ther. 2019 Feb 6;27(2):424-441. doi: 10.1016/j.ymthe.2018.09.019. Epub 2018 Oct 4.

Authors

Affiliations

¹ Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia. Electronic address: nitin.chitranshi@mq.edu.au.
² Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia.
³ Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia; Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia; Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia.
⁴ Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia.
⁵ School of Medicine, Deakin University, Geelong, VIC, Australia.
⁶ Save Sight Institute, Sydney University, Sydney, NSW, Australia.
⁷ Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia; Save Sight Institute, Sydney University, Sydney, NSW, Australia.
⁸ Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia. Electronic address: vivek.gupta@mq.edu.au.

Abstract

Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling. This was elucidated by specifically modulating Shp2 expression in the RGCs in vivo, using adeno-associated virus serotype 2 (AAV2) constructs. Shp2 upregulation promoted endoplasmic reticulum (ER) stress and apoptosis, along with functional and structural deficits in the inner retina. In contrast, loss of Shp2 decelerated the loss of RGCs, preserved their function, and suppressed ER stress and apoptosis in glaucoma. This report constitutes the first identification of Shp2-mediated TrkB regulatory mechanisms in the RGCs that can become a potential therapeutic target in both glaucoma and other neurodegenerative disorders.

Keywords: AAV2; BDNF/TrkB; ER stress; RGCs; Shp2; apoptosis; gene delivery; glaucoma; retina.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Brain-Derived Neurotrophic Factor / genetics
Brain-Derived Neurotrophic Factor / metabolism*
Disease Models, Animal
Electrophoresis, Polyacrylamide Gel
Electroretinography
Glaucoma / metabolism
Glaucoma / pathology
Male
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
Rats
Rats, Sprague-Dawley
Receptor, trkB / genetics
Receptor, trkB / metabolism*
Retina / cytology
Retina / metabolism
Retinal Ganglion Cells / metabolism*
Retinal Ganglion Cells / physiology
Signal Transduction / genetics
Signal Transduction / physiology

Substances

Brain-Derived Neurotrophic Factor
Ntrk2 protein, rat
Receptor, trkB
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Ptpn11 protein, rat