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Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma

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Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma. / Chitranshi, Nitin; Rajput, Rashi; Godinez, Angela; Pushpitha, Kanishka; Mirzaei, Mehdi; Basavarajappa, Devaraj; Gupta, Veer; Sharma, Samridhi; You, Yuyi; Galliciotti, Giovanna; Salekdeh, Ghasem H; Baker, Mark; Graham, Stuart L; Gupta, Vivek K.

In: MOL THER, Vol. 31, No. 7, 05.07.2023, p. 2056-2076.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Chitranshi, N, Rajput, R, Godinez, A, Pushpitha, K, Mirzaei, M, Basavarajappa, D, Gupta, V, Sharma, S, You, Y, Galliciotti, G, Salekdeh, GH, Baker, M, Graham, SL & Gupta, VK 2023, 'Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma', MOL THER, vol. 31, no. 7, pp. 2056-2076. https://doi.org/10.1016/j.ymthe.2023.03.008

APA

Chitranshi, N., Rajput, R., Godinez, A., Pushpitha, K., Mirzaei, M., Basavarajappa, D., Gupta, V., Sharma, S., You, Y., Galliciotti, G., Salekdeh, G. H., Baker, M., Graham, S. L., & Gupta, V. K. (2023). Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma. MOL THER, 31(7), 2056-2076. https://doi.org/10.1016/j.ymthe.2023.03.008

Vancouver

Chitranshi N, Rajput R, Godinez A, Pushpitha K, Mirzaei M, Basavarajappa D et al. Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma. MOL THER. 2023 Jul 5;31(7):2056-2076. https://doi.org/10.1016/j.ymthe.2023.03.008

Bibtex

@article{c496a3c9a7254773bcaba43c404b5a9d,
title = "Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma",
abstract = "Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.",
author = "Nitin Chitranshi and Rashi Rajput and Angela Godinez and Kanishka Pushpitha and Mehdi Mirzaei and Devaraj Basavarajappa and Veer Gupta and Samridhi Sharma and Yuyi You and Giovanna Galliciotti and Salekdeh, {Ghasem H} and Mark Baker and Graham, {Stuart L} and Gupta, {Vivek K}",
note = "Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = jul,
day = "5",
doi = "10.1016/j.ymthe.2023.03.008",
language = "English",
volume = "31",
pages = "2056--2076",
journal = "MOL THER",
issn = "1525-0016",
publisher = "NATURE PUBLISHING GROUP",
number = "7",

}

RIS

TY - JOUR

T1 - Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma

AU - Chitranshi, Nitin

AU - Rajput, Rashi

AU - Godinez, Angela

AU - Pushpitha, Kanishka

AU - Mirzaei, Mehdi

AU - Basavarajappa, Devaraj

AU - Gupta, Veer

AU - Sharma, Samridhi

AU - You, Yuyi

AU - Galliciotti, Giovanna

AU - Salekdeh, Ghasem H

AU - Baker, Mark

AU - Graham, Stuart L

AU - Gupta, Vivek K

N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2023/7/5

Y1 - 2023/7/5

N2 - Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.

AB - Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.

U2 - 10.1016/j.ymthe.2023.03.008

DO - 10.1016/j.ymthe.2023.03.008

M3 - SCORING: Journal article

C2 - 36905120

VL - 31

SP - 2056

EP - 2076

JO - MOL THER

JF - MOL THER

SN - 1525-0016

IS - 7

ER -