Diabetic retinopathy (DR) is among the leading causes of preventable blindness in developed countries. Current treatments target the late stages of DR, when visual acuity, however, has already been significantly impaired.
DR has long been considered an exclusively microcirculatory retinal pathology; however, current research suggests that retinal neurodegeneration, leading to a significant thinning of the retinal nerve cell layer, may be a early event in the pathogenesis of DR and influence the development of microvascular abnormalities.
Neuronal apoptosis and glial activation (GA) are the most important histological features of retinal neurodegeneration. GA is the general response to glial cell injury and is characterised by abnormal expression of the fibrillary acid glia protein (GFAP). This protein is expressed, in the normal retina, mainly by astrocytes and to a small extent by Müller cells. In the diabetic condition, the reverse situation occurs, Müller cells acquire significant immunoreactivity to GFAPwhile astrocytes progressively lose expression of GFAP. It should be noted that Müller cellsthe main glial cells of the retina, produce factors capable of modulating blood flow, vascular permeability and cell survival. These processes occur in the vicinity of the blood vessels of the retina, so a lesion in these cells plays an essential role in the pathogenesis of early microcirculation abnormalities and neurovascular impairment of the retina. GA can also induce neural cell death.
Most of the cellular and molecular knowledge of the mechanisms involved in the early stages of DR comes from experimental models, but these give little indication of the biochemical changes that occur in the retina of the diabetic patient before the onset of clinically observable abnormalities.
The study by Sundstrom and colleagues, identified, through a proteomic approach, the main proteins and metabolic pathways involved in the early stages of DR. The study was conducted by comparing control retinas of non-diabetic donors (C) with diabetic retinas of patients without classical vascular lesions that clinically define DR.
The study focused on the analysis of the most relevant proteins linked to neuroregulatory and neurodegenerative pathways unique to each of the three groups (control and diabetic retinas with and without GA), with a focus on proteins and pathways shared with neurodegenerative diseases of the central nervous system.
They have been identified 2190 proteins in totalin all groups. To assess the association of the identified proteins with neurological signalling pathways, the researchers selected the most significant pathways belonging to the category defined as 'Neurotransmitters and other signals of the nervous system". With this approach, the presence or absence of pathways involved in neuroregulatory cell functions was identified in each group. In general, significant homology was observed between all three groups with a total of 73 shared pathways (58% of the total). However, for each group, a considerable number of unique neurological pathways were identified.
In the non-diabetic control group (C), the pathways 'Neuroprotective role of THOP1 in Alzheimer's disease' and 'Unfolded protein response' were uniquely present. In the diabetic retina group with GA (D), the pathways 'Dopamine degradation' and 'Parkinson's signalling' were most present; whereas, in the diabetic retina group without GA (DþGFAP), the pathways most present were 'Neuregulin signalling', 'Long-term synaptic potentiation' and 'Amyeloid processing'.
The study identified a total of 35 pathways related to neurodegeneration or neuroregulation specifically represented in a single group (C, D and DþGFAP). Some of these, moreover, are pathways shared with other neurodegenerative disorders, such as Alzheimer's and Parkinson's diseasethereby supporting the existence of a common ground between neurodegenerative processes occurring in the retina and the brain.
The work highlighted not only proteome changes that occur in the early stages of DR, but also, based on the degree of GFAP immunoreactivity in each group, how these processes vary with disease severity. Upregulation of GFAP, for example, corresponds to glial activation (GA), a pathological change associated with neurodegeneration and preceding the microvascular abnormalities evident in DR.
Thus, a better understanding of the pathogenesis of DR would allow the development of more effective preventive and interventional strategies against the early stages of the diseasebefore microvascular damage and visual impairment occur. Studies on the neurodegeneration of the diabetic retina could also open up avenues for understanding the neurodegenerative processes occurring in the central nervous system of diabetic patients.
Source
Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases. JM Sundstrom et al. Invest Ophthalmol Vis Sci. 2018, May; 59(6): 2264-2274.
Dr. Carmelo Chines
Direttore responsabile
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