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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages424-441
Number of pages18
JournalMolecular Therapy
Volume27
Issue number2
DOIs
Publication statusPublished - 6 Feb 2019

Fingerprint

trkB Receptor
Retinal Ganglion Cells
Glaucoma
Endoplasmic Reticulum Stress
Apoptosis
Protein Phosphatase 2
Dependovirus
Protein Tyrosine Phosphatases
Neurodegenerative Diseases
Axons
Retina
Up-Regulation
Animal Models
Neuroprotection
tropomyosin kinase
Survival
Therapeutics

Keywords

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

Cite this

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title = "Loss of Shp2 rescues BDNF/TrkB signaling and contributes to improved retinal ganglion cell neuroprotection",
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.",
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author = "Nitin Chitranshi and Yogita Dheer and Mehdi Mirzaei and Yunqi Wu and Salekdeh, {Ghasem H.} and Mojdeh Abbasi and Veer Gupta and {Vander Wall}, Roshana and Yuyi You and Graham, {Stuart L.} and Vivek Gupta",
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Loss of Shp2 rescues BDNF/TrkB signaling and contributes to improved retinal ganglion cell neuroprotection. / Chitranshi, Nitin; Dheer, Yogita; Mirzaei, Mehdi; Wu, Yunqi; Salekdeh, Ghasem H.; Abbasi, Mojdeh; Gupta, Veer; Vander Wall, Roshana; You, Yuyi; Graham, Stuart L.; Gupta, Vivek.

In: Molecular Therapy, Vol. 27, No. 2, 06.02.2019, p. 424-441.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Loss of Shp2 rescues BDNF/TrkB signaling and contributes to improved retinal ganglion cell neuroprotection

AU - Chitranshi, Nitin

AU - Dheer, Yogita

AU - Mirzaei, Mehdi

AU - Wu, Yunqi

AU - Salekdeh, Ghasem H.

AU - Abbasi, Mojdeh

AU - Gupta, Veer

AU - Vander Wall, Roshana

AU - You, Yuyi

AU - Graham, Stuart L.

AU - Gupta, Vivek

PY - 2019/2/6

Y1 - 2019/2/6

N2 - 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.

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