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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)424-441
Number of pages18
JournalMolecular Therapy
Volume27
Issue number2
DOIs
Publication statusPublished - 6 Feb 2019

Keywords

  • AAV2
  • apoptosis
  • BDNF/TrkB
  • ER stress
  • gene delivery
  • glaucoma
  • retina
  • RGCs
  • Shp2

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