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

ABSTRACT: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. Despite the success of anti-VEGF therapy as an effective therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players. To unveil these, we performed deep vitreous proteome profiling of patients with proliferative DR and extracted aberrated protein networks. This revealed impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, that pointed to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in ocular disease models and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified impaired ADAM10-AXL axis as a retinal angiogenic driver. Taken together, we demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating DR and propose ADAM10 as an attractive novel target.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Vitreous Humor

DISEASE(S): Proliferative Diabetic Retinopathy

SUBMITTER: Asfa Alli Shaik  

LAB HEAD: Jayantha Gunaratne

PROVIDER: PXD036033 | Pride | 2022-10-14

REPOSITORIES: Pride