Investigation of the mechanisms of photoreceptor degeneration

The Macular Research Group (MRG) at the Save Sight Institute has set itself the goal of developing new treatments for macular diseases through first-class, patient-oriented research. A recent MRG study focused on the mechanisms of photoreceptor degeneration that occurs in many blind conditions such as age-related macular degeneration (AMD).

This study examined the relationship between Müllerian glia (a type of retinal cell) and photoreceptor degeneration. The retina is one of the most metabolically active tissues in the body. Photoreceptors are cells in the retina that respond to light. These cells lose 10% of their outer segment every day and need energy and metabolic products to constantly renew themselves. A disturbance of the external metabolism of the retina can lead to degeneration of the photoreceptors and consequently to blind eye diseases.

Muller glia can be important in supporting photoreceptors.

The close anatomical relationship between Mueller glia and the photoreceptors suggests that Mueller glia can provide important metabolites to support the photoreceptors. A better understanding of how Mueller glia metabolically supports the photoreceptors could provide new insights into the mechanisms of photoreceptor degeneration.

To test this idea, the team generated a transgenic mouse model. Transgenic models are created by deliberately inserting a foreign gene into the animal’s genome. This model was developed to specifically target individual components of the metabolic process in the Müllerian glia and to study the effects on the health of the photoreceptors. When they found out that Muller glia can use glucose to produce serine to support photoreceptors, they also investigated the effect of serine supplements on photoreceptor degeneration.

The study used selective gene targeting of transgenic mice, immunofluorescence staining of retinal sections, free-floating staining of the entire retina, Western blot analysis of protein expression in the retina, primary cell cultures, color fundus photography, electroretinography (ERG) and gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry for the analysis of retinal metabolites.

The team first looked at which metabolic genes are expressed by Mueller glia and found that they express insulin receptor (IR), hexokinase 2 (HK2), and phosphoglycerate dehydrogenase (PHGDH). Each of these proteins play a key role in regulating glucose homeostasis. Glucose homeostasis is critical to human health because of the central importance of glucose as an energy source. Regulating blood sugar levels is critical to eye health, as high blood sugar can lead to problems such as blurred vision, cataracts, glaucoma, and retinopathy.

They then created transgenic animals in which these proteins could be selectively targeted, and found that the selective breakdown of IR, HK2 or PHGDH led to photoreceptor degeneration and reduced photoreceptor function. They also found that serine supplementation prevented photoreceptor degeneration and improved retinal function in animals with PHGDH deficiency. They believe that the mechanism of this rescue is through the regulation of serine transport.

Taken together, these results suggest that Muller glia uses glucose to produce serine to support photoreceptors. Further research is still important to elucidate the complex relationship between Muller glia and photoreceptors.

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