System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy

System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy

Theranostics

10.7150/thno.72947

http://dx.doi.org/10.7150/thno.72947

Asfa Alli-Shaik, Beiying Qiu, Siew Li Lai, Ning Cheung, Gavin Tan, Suat Peng Neo, Alison Tan, Chiu Ming Gemmy Cheung, Wanjin Hong, Tien Yin Wong, Xiaomeng Wang, Jayantha Gunaratne

28 September 2022

Alli-Shaik, A., Qiu, B., Lai, S. L., Cheung, N., Tan, G., Neo, S. P., Tan, A., Cheung, C. M. G., Hong, W., Wong, T. Y., Wang, X., & Gunaratne, J. (2022). System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy. Theranostics, 12(15), 6682–6704. https://doi.org/10.7150/thno.72947

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possi

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the Singapore Biomedical Research Council - Strategic Positioning Fund
Grant Reference no. : BMRC-SPF-SIPRAD;SPF-SIPRAD-2014/002

This research / project is supported by the National Medical Research Council Singapore - Large Collaborative Grant TAAP
Grant Reference no. : NMRC/OFLCG/004/2018

This research / project is supported by the Singapore Ministry of Health's / National Medical Research Council (NMRC) - Open Fund - Young Individual Research Grant
Grant Reference no. : MOH-000539

This research is supported by core funding from: Institute of Molecular and Cell Biology (IMCB)
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/20303

1838-7640

Institute of Molecular and Cell Biology

https://dx.doi.org/10.7150/thno.72947