Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases

Purpose: Current evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy. Our main goal was to examine whether, in the diabetic human retina, common proteins and pathways are shared with brain neurodegenerative diseases. Methods: A proteomic analysis was performed on three groups of postmortem retinas matched by age: nondiabetic control retinas (n = 5), diabetic retinas without glial activation (n = 5), and diabetic retinas with glial activation (n = 5). Retinal lysates from each group were pooled and run on an SDS-PAGE gel. Bands were analyzed sequentially by liquid chromatography-mass spectrometry (LC/MS) using an Orbitrap Mass Spectrometer. Results: A total of 2190 proteins were identified across all groups. To evaluate the association of the identified proteins with neurological signaling, significant signaling pathways belonging to the category “Neurotransmitters and Other Nervous System Signaling” were selected for analysis. Pathway analysis revealed that “Neuroprotective Role of THOP1 in Alzheimer's Disease” and “Unfolded Protein Response” pathways were uniquely enriched in control retinas. By contrast, “Dopamine Degradation” and “Parkinson's Signaling” were enriched only in diabetic retinas with glial activation. The “Neuregulin Signaling,” “Synaptic Long Term Potentiation,” and “Amyloid Processing” pathways were enriched in diabetic retinas with no glial activation. Conclusions: Diabetes-induced retinal neurodegeneration and brain neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, share common pathogenic pathways. These findings suggest that the study of neurodegeneration in the diabetic retina could be useful to further understand the neurodegenerative processes that occur in the brain of persons with diabetes.