AAV2-mediated GRP78 transfer alleviates retinal neuronal injury by downregulating ER stress and Tau oligomer formation

Yonju Ha, Wei Liu, Hua Liu, Shuang Zhu, Fan Xia, Julia E. Gerson, Nisha A. Azhar, Ronald Tilton, Massoud Motamedi, Rakez Kayed, Wenbo Zhang

Research output: Contribution to journalArticle

Abstract

PURPOSE. Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). METHODS. ONC was induced by a transient crush of optic nerve behind the eye globe. AAV was used to deliver genes into retina. Molecules in the ER stress branches, tau oligomers, and RGC injury were determined by immunohistochemistry or Western blot. RESULTS. Among tested AAV serotypes, AAV2 was the most efficient for delivering genes to RGCs. Intravitreal delivery of AAV2-GRP78 markedly attenuated ER stress and RGC death 3 days after ONC, and significantly improved RGC survival and function 7 days after ONC. Protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases. AAV2-GRP78 alleviated ONC-induced increases in tau phosphorylation and oligomerization. Furthermore, tau oligomers directly induced RGC death, and blocking tau oligomers with tau oligomer monoclonal antibody (TOMA) attenuated ONC-induced RGC loss. CONCLUSION. These data indicate that the beneficial effect of AAV2-GRP78 is partially mediated by the reduction of misfolded tau, and provide compelling evidence that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offers novel therapeutic approaches to alleviate RGC loss in TON.

LanguageEnglish (US)
Pages4670-4682
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number11
DOIs
StatePublished - Sep 1 2018

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Endoplasmic Reticulum Stress
Nerve Crush
Retinal Ganglion Cells
Optic Nerve
Down-Regulation
Optic Nerve Injuries
Wounds and Injuries
Dependovirus
Cell Death
Monoclonal Antibodies
Genes
Molecular Chaperones
Protein Folding
Heat-Shock Proteins
Neurodegenerative Diseases
Genetic Therapy
Immunotherapy
Retina
Cell Survival
Western Blotting

Keywords

  • Adeno-associated virus
  • Endoplasmic reticulum stress
  • GRP78
  • Retinal ganglion cell
  • Tau oligomers
  • Traumatic optic neuropathy

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

AAV2-mediated GRP78 transfer alleviates retinal neuronal injury by downregulating ER stress and Tau oligomer formation. / Ha, Yonju; Liu, Wei; Liu, Hua; Zhu, Shuang; Xia, Fan; Gerson, Julia E.; Azhar, Nisha A.; Tilton, Ronald; Motamedi, Massoud; Kayed, Rakez; Zhang, Wenbo.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 11, 01.09.2018, p. 4670-4682.

Research output: Contribution to journalArticle

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abstract = "PURPOSE. Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). METHODS. ONC was induced by a transient crush of optic nerve behind the eye globe. AAV was used to deliver genes into retina. Molecules in the ER stress branches, tau oligomers, and RGC injury were determined by immunohistochemistry or Western blot. RESULTS. Among tested AAV serotypes, AAV2 was the most efficient for delivering genes to RGCs. Intravitreal delivery of AAV2-GRP78 markedly attenuated ER stress and RGC death 3 days after ONC, and significantly improved RGC survival and function 7 days after ONC. Protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases. AAV2-GRP78 alleviated ONC-induced increases in tau phosphorylation and oligomerization. Furthermore, tau oligomers directly induced RGC death, and blocking tau oligomers with tau oligomer monoclonal antibody (TOMA) attenuated ONC-induced RGC loss. CONCLUSION. These data indicate that the beneficial effect of AAV2-GRP78 is partially mediated by the reduction of misfolded tau, and provide compelling evidence that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offers novel therapeutic approaches to alleviate RGC loss in TON.",
keywords = "Adeno-associated virus, Endoplasmic reticulum stress, GRP78, Retinal ganglion cell, Tau oligomers, Traumatic optic neuropathy",
author = "Yonju Ha and Wei Liu and Hua Liu and Shuang Zhu and Fan Xia and Gerson, {Julia E.} and Azhar, {Nisha A.} and Ronald Tilton and Massoud Motamedi and Rakez Kayed and Wenbo Zhang",
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T1 - AAV2-mediated GRP78 transfer alleviates retinal neuronal injury by downregulating ER stress and Tau oligomer formation

AU - Ha, Yonju

AU - Liu, Wei

AU - Liu, Hua

AU - Zhu, Shuang

AU - Xia, Fan

AU - Gerson, Julia E.

AU - Azhar, Nisha A.

AU - Tilton, Ronald

AU - Motamedi, Massoud

AU - Kayed, Rakez

AU - Zhang, Wenbo

PY - 2018/9/1

Y1 - 2018/9/1

N2 - PURPOSE. Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). METHODS. ONC was induced by a transient crush of optic nerve behind the eye globe. AAV was used to deliver genes into retina. Molecules in the ER stress branches, tau oligomers, and RGC injury were determined by immunohistochemistry or Western blot. RESULTS. Among tested AAV serotypes, AAV2 was the most efficient for delivering genes to RGCs. Intravitreal delivery of AAV2-GRP78 markedly attenuated ER stress and RGC death 3 days after ONC, and significantly improved RGC survival and function 7 days after ONC. Protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases. AAV2-GRP78 alleviated ONC-induced increases in tau phosphorylation and oligomerization. Furthermore, tau oligomers directly induced RGC death, and blocking tau oligomers with tau oligomer monoclonal antibody (TOMA) attenuated ONC-induced RGC loss. CONCLUSION. These data indicate that the beneficial effect of AAV2-GRP78 is partially mediated by the reduction of misfolded tau, and provide compelling evidence that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offers novel therapeutic approaches to alleviate RGC loss in TON.

AB - PURPOSE. Retinal ganglion cell (RGC) death following axonal injury occurring in traumatic optic neuropathy (TON) causes irreversible vision loss. GRP78 is a molecular chaperone that enhances protein folding and controls activation of endoplasmic reticulum (ER) stress pathways. This study determined whether adeno-associated virus (AAV)-mediated gene transfer of GRP78 protected RGCs from death in a mouse model of TON induced by optic nerve crush (ONC). METHODS. ONC was induced by a transient crush of optic nerve behind the eye globe. AAV was used to deliver genes into retina. Molecules in the ER stress branches, tau oligomers, and RGC injury were determined by immunohistochemistry or Western blot. RESULTS. Among tested AAV serotypes, AAV2 was the most efficient for delivering genes to RGCs. Intravitreal delivery of AAV2-GRP78 markedly attenuated ER stress and RGC death 3 days after ONC, and significantly improved RGC survival and function 7 days after ONC. Protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases. AAV2-GRP78 alleviated ONC-induced increases in tau phosphorylation and oligomerization. Furthermore, tau oligomers directly induced RGC death, and blocking tau oligomers with tau oligomer monoclonal antibody (TOMA) attenuated ONC-induced RGC loss. CONCLUSION. These data indicate that the beneficial effect of AAV2-GRP78 is partially mediated by the reduction of misfolded tau, and provide compelling evidence that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offers novel therapeutic approaches to alleviate RGC loss in TON.

KW - Adeno-associated virus

KW - Endoplasmic reticulum stress

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KW - Retinal ganglion cell

KW - Tau oligomers

KW - Traumatic optic neuropathy

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