Inhibiting post-translational modifications may lower oxidative stress in the aging eye

Retinal pigment epithelial (RPE) cells are a pigmented cells present in a monolayer outside the retinal. These cells are essential for absorbing scattered light in the eye and maintain visual function. As a person ages, these cells can die without, causing age-related macular degeneration (AMD), a blinding eye disease that affects more than 30 million people worldwide. Oxidative stress-induced RPE cell senescence is considered as one the greatest risk factors contributing to the onset of AMD. Other factors include hereditary factors which modulate inflammation.

Most cellular processes are regulated by the expression of genes into specific proteins. Some proteins (such as SUMO proteins) can modify existing proteins to trigger cellular processes. Cell senescence is such a process and this is believed to be regulated by SUMOylation – an essential post-translational modification reaction in vertebrates – which results in the conjugation of SUMO proteins to target proteins involved in the process.

A team of researchers from the Zhongshan Ophthalmology Center, Guangzhou, China, led by Dr. David W. Li and Dr. Lili Gong, studied SUMOylation processes in mouse retinae in an effort to investigate cell senescence in RPE cells. The researchers found decreased SUMO ligase expression in aging mouse retina samples and in senescent RPE cells, a finding which indicates reduced global protein SUMOylation levels. Interestingly, the researchers also learned that the localized distribution of SUMO ligases, such as E1 enzyme UBA2, E2 enzyme UBC9, was dramatically changed during the oxidative stress-induced RPE cell senescence. “This altered distribution of the major SUMO machinery suggests that the SUMOylation substrates may be altered and both loss of SUMOylation and an increase in new SUMOylation products may occur during cell senescence,” says Dr. Lili. The researchers believe that in addition to decreased SUMOylation levels, SUMOylation targets in senescent cells are likely different from those in young cells and this difference may be accounted for by the spatial regulation of SUMO ligases within RPE cells.

Additionally, the researchers investigated the inhibition of SUMOylation with two small molecules and ML792 (that targets the SUMO E1 enzyme). Their results indicate that ML792 treatment alleviated the expression of senescence associated secretory phenotype (SASP) genes – or in other words, the aged cell variants – in RPE cells, as several proinflammatory factor was observed to be down-regulated by ML972 treatment. “This is the first report that shows that inhibition of SUMOylation has reduced SASP, expression”, notes Dr. Lili. Their research can grow the understanding of AMD pathogenesis and lead to new avenues for treatment. Dr. Lili adds that “it is very intriguing considering the effects of SASP factors in compromising RPE cell barrier functions and resulting in immune cell invasion, which contributes to the severity of retina degeneration and AMD pathogenesis.”

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