OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

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Publication Details

Journal
Communications Biology
Published
2025-10-16
DOI
https://doi.org/10.1038/s42003-025-08534-6
Primary Topic
Glaucoma and retinal disorders
Type
article
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article

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies

Guangmei Cao, Fengfeng Bei, Jin Hao, Wensheng Yan et al.
Communications Biology
Glaucoma and retinal disorders
article

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies

Guangmei Cao, Fengfeng Bei, Jin Hao, Wensheng Yan, Yong‐hui Jiang, Ryan Donahue, Qianbin Wang, Yiqi Wang, Qinglong Wang, Hong Guo, Zhenghui Li, Feng Tian, Jingli Liang, Yi Lu
article en

Abstract

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

Communications BiologyVol. 8(1)
Tufts University (US), Binghamton University (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), Georgia Institute of Technology (US), Beth Israel Deaconess Medical Center (US), Harvard University (US), Duke Medical Center (US), Duke University Hospital (US)
Openalex Percentile: Top 57%
Glaucoma and retinal disorders
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