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Aqueous humor protein dysregulation in primary angle-closure glaucoma

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Abstract

Purpose

Primary angle-closure glaucoma (PACG) is associated with increased intraocular pressure, optic nerve damage, and progressive vision loss, but the molecular mechanism that underpins retinal ganglion neuropathy in PACG remains poorly understood. To better understand the pathogenesis of human PACG, we performed the first comprehensive proteomic analysis of aqueous humor (AH) samples from PACG patients and matched control donors to study pathogenic alteration in AH composition in disease.

Methods

High-resolution, label-free, liquid chromatography–tandem mass spectrometry-based quantitative proteomic analyses were performed in AH samples collected from PACG patients and a matched control cohort of patients with cataracts.

Results

The AH proteome comprised of 1363 distinct proteins, of which more than 50% were differentially expressed in PACG (773 total; 501 up-regulated, 272 down-regulated). AH from PACG patients was enriched in atypical collagens and fibronectins, suggesting that the composition of the trabecular matrix is significantly altered in disease. Pathway and cluster analyses revealed that AH protein modulation in PACG is closely associated with biological processes including platelet degranulation, cellular import/export mechanisms, and control of protease activity. In addition, critical mediators of oxygen homeostasis and neuronal function in AH were significantly dysregulated in disease, strongly implicating oxidative stress responses in PACG-associated nerve damage.

Conclusions

Altered AH proteome in human PACG indicated oxidative stress in the neuronal damage that preceded vision loss. Identifying key mediators of PACG pathology will yield new prognostic biomarkers and novel targets for future therapeutic interventions.

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Acknowledgements

This work is in part supported by grants from the Singapore Ministry of Education (MOE2014-T2-2-043 and MOE2016-T2-2-018), the National Medical Research Council of Singapore (NMRC-OF-IRG-0003-2016), and National Healthcare Group Small Innovative Grant (Grant # 13018).

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Author notes

  1. Sunil S. Adav and Jin Wei have contributed equally to this work.

Authors and Affiliations

  1. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore

    Sunil S. Adav, Jin Wei, Jingru Qian & Siu Kwan Sze

  2. Eye Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China

    Jin Wei

  3. Department of Ophthalmology, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore

    Nicola Yi’An Gan & Leonard W. L. Yip

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  1. Sunil S. Adav
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  2. Jin Wei
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  4. Nicola Yi’An Gan
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  5. Leonard W. L. Yip
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  6. Siu Kwan Sze
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Correspondence to Leonard W. L. Yip or Siu Kwan Sze.

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This study was in agreement with the Declaration of Helsinki and approved by the Institutional Review Board at the Tan Tock Seng Hospital (TTSH). Informed consent was obtained from each patient.

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Adav, S.S., Wei, J., Qian, J. et al. Aqueous humor protein dysregulation in primary angle-closure glaucoma. Int Ophthalmol 39, 861–871 (2019). https://doi.org/10.1007/s10792-018-0885-3

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