WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma

WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision loss. On exam visual acuities were at 20/100 level, had a tritan color defect and showed central arcuate visual field defects on visual field testing. Enlarged cup-to-disk ratios with normal intraocular pressures were associated with severe thinning of the ganglion cell layer (GCL) and retinal nerve fiber layer consistent with a clinical diagnosis of normal tension glaucoma. Full-field electroretinograms revealed a severe inner retinal dysfunction with reduced amplitudes and remarkably delayed timings of the b-wave, but preserved photoreceptor (a-wave) function. The pattern described herein recapitulates some of the findings of an animal model of WDR36-associated POAG and suggests a mechanism of disease that involves a retina-wide inner retinal dysfunction and neurodegeneration beyond the GCL. Further detailed structural and functional characterizations of patients with a pathogenic variant in the WDR36 gene are required to confirm these findings.

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

Retinal Dysfunction in Alzheimer’s Disease and Implications for Biomarkers

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests as cognitive deficits and memory decline, especially in old age. Several biomarkers have been developed to monitor AD progression. Given that the retina and brain share some similarities including features related to anatomical composition and neurological functions, the retina is closely associated with the progression of AD. Herein, we review the evidence of retinal dysfunction in AD, particularly at the early stage, together with the underlying molecular mechanisms. Furthermore, we compared the retinal pathologies of AD and other ophthalmological diseases and summarized potential retinal biomarkers measurable by existing technologies for detecting AD, providing insights for the future development of diagnostic tools.

The Timecourses of Functional, Morphological, and Molecular Changes Triggered by Light Exposure in Sprague–Dawley Rat Retinas

Retinal neurodegeneration can impair visual perception at different levels, involving not only photoreceptors, which are the most metabolically active cells, but also the inner retina. Compensatory mechanisms may hide the first signs of these impairments and reduce the likelihood of receiving timely treatments. Therefore, it is essential to characterize the early critical steps in the neurodegenerative progression to design adequate therapies. This paper describes and correlates early morphological and biochemical changes in the degenerating retina with in vivo functional analysis of retinal activity and investigates the progression of neurodegenerative stages for up to 7 months. For these purposes, Sprague–Dawley rats were exposed to 1000 lux light either for different durations (12 h to 24 h) and examined seven days afterward (7d) or for a fixed duration (24 h) and monitored at various time points following the exposure (up to 210d). Flash electroretinogram (fERG) recordings were correlated with morphological and histological analyses to evaluate outer and inner retinal disruptions, gliosis, trophic factor release, and microglial activation. Twelve hours or fifteen hours of exposure to constant light led to a severe retinal dysfunction with only minor morphological changes. Therefore, early pathological signs might be hidden by compensatory mechanisms that silence retinal dysfunction, accounting for the discrepancy between photoreceptor loss and retinal functional output. The long-term analysis showed a transient functional recovery, maximum at 45 days, despite a progressive loss of photoreceptors and coincident increases in glial fibrillary acidic protein (GFAP) and basic fibroblast growth factor-2 (bFGF-2) expression. Interestingly, the progression of the disease presented different patterns in the dorsal and ventral retina. The information acquired gives us the potential to develop a specific diagnostic tool to monitor the disease’s progression and treatment efficacy.