Zhejiang University JBC publishes new findings in biochemical research

Researchers from Zhejiang University identified a new lipofuscin component iisoA2E in the retina and determined its effect on retinal pigment epithelial cells. Related research results were published in the October 29th "Journal of Biochemistry" (JBC).

The corresponding author of the article is Dr. Yalin Wu, a special researcher at the School of Pharmacy, Zhejiang University. His main research directions include the pathogenesis and treatment of macular degeneration diseases; centripetal ligands and receptor proteins during visual signal transduction Interaction research; research and development of natural drugs for targeted treatment of diseases (mainly fundus macular degeneration).

Vision relies on the attachment of a biopigment made of opsin to the chromophore. The visual chromophore of most vertebrate opsins is 11-cis-retinal. After capturing the image through the opsin pigment, 1-cis-retinal binds to the 296th lysine of opsin and isomerizes to all-trans-retinal. Restoring photosensitivity to bleached opsin pigments involves an isomerization of all-trans-retinal to 11-cis-retinal via an enzymatic process called the visual cycle.

Most visual cycle steps occur in retinal pigment epithelium (RPE) cells. The visual cycle generates a large amount of retinoids, which can lead to increased levels of toxic retinoids, especially all-trans-retinal, causing degradation of photoreceptors. Studies have pointed out that the precursor of dual retinoids, all-trans-retinal, can trigger caspase activation and mitochondrial-related cell death, which is related to the complicated pathogenesis of Stargardt disease and age-related macular degeneration (AMD).

Another function of RPE cells is to engulf the outer end of the photoreceptor (POS), and the photoreceptor cells fall off the end of the POS every day. Based on these functions, RPE is essential for maintaining photoreceptor activity. The continuous shedding of terminal POS and phagocytosis have resulted in the accumulation of fluorescent retinoids, lipids and lipofuscin in RPE phagolysosomes. The harmful accumulation of lipofuscin in the eyes is regarded as a causative agent of blindness in patients with retinopathy, especially AMD and Stargardt disease.

A2E is the first described RPE lipofuscin component, it is a pyridine diretinol. Previous studies have revealed that excessive accumulation of A2E in REP cells can mediate detergent-like effects on the cell membrane, leading to lysosomal alkalization and separation of pro-apoptotic proteins from mitochondria. In addition, studies have determined that in the absence of light exposure, 11-cis-retinal is the main source of lipofuscin. Understanding the components of RPE lipofuscin and the biosynthetic signaling pathways formed by these complexes is helpful in understanding retinopathy caused by excessive amounts of toxic lipofuscin.

In this article, the researchers discovered a component of PRE lipofuscin that was previously unknown. Through one-dimensional and two-dimensional NMR techniques and mass spectrometry, the researchers confirmed that this compound is a new class of pyridine diretinol, which has an unusual structure. This pigment is a light-induced isoform of isoA2E, called iisoA2E. This pigment is a fluorescent lipofuscin compound with a maximum absorbance of ~ 430 and 352nm detected in human, pig, mouse and cow eyes.

The study found that iisoA2E was formed in the reaction mixture of all-trans-retinal and ethanolamine. The excessive accumulation of this addition compound in RPE cells resulted in a significant loss of cell viability and caused membrane damage. In addition, the new research also revealed the biosynthetic pathway of iisoA2E and the mechanism by which isoA2E is transformed into this isoform by light.

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