Abstract
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly population. Hypoxic stress created in the micro-environment of the photoreceptors is thought to be the underlying cause that results in the pathophysiology of AMD. However, association of AMD with alternative splicing mediated gene regulation is not well explored. Alternative Splicing is one of the primary mechanisms in humans by which fewer protein coding genes are able to generate a vast proteome. Here, we investigated the expression of a known stress response gene and an alternative splicing factor called Serine-Arginine rich splicing factor 10 (Sfrs10). Sfrs10 is a member of the serine-arginine (SR) rich protein family and is 100% identical at the amino acid level in most mammals. Immunoblot analysis on retinal extracts from mouse, rat, and chicken showed a single immunoreactive band. Further, immunohistochemistry on adult mouse, rat and chicken retinae showed pan-retinal expression. However, SFRS10 was not detected in normal human retina but was observed as distinct nuclear speckles in AMD retinae. This is in agreement with previous reports that show Sfrs10 to be a stress response gene, which is upregulated under hypoxia. The difference in the expression of Sfrs10 between humans and lower mammals and the upregulation of SFRS10 in AMD is further reflected in the divergence of the promoter sequence between these species. Finally, SFRS10+ speckles were independent of the SC35+ SR protein speckles or the HSF1+ stress granules. In all, our data suggests that SFRS10 is upregulated and forms distinct stress-induced speckles and might be involved in AS of stress response genes in AMD.
Highlights
Age-related Macular degeneration (AMD) is the leading cause of blindness in the aging population in the developed world
Our study focuses on another member of the SR family called Serine-Arginine rich splicing factor 10 (SFRS10), a known stress response gene
Sfrs10 is an alternative splicing factors (ASFs) that has been shown to respond to episodes of hypoxic/ oxidative stress and so we investigated the expression of SFRS10 in AMD retinae
Summary
Age-related Macular degeneration (AMD) is the leading cause of blindness in the aging population in the developed world. The underlying cause of AMD is thought to be the hypoxic condition experienced by the photoreceptors leading to their degeneration [1,2,3,4,5,6,7]. Rod photoreceptors consume more O2 per gram of tissue weight than any other cell in the body [8] This constant high energy demand makes the photoreceptors more susceptible to hypoxic stress. Factors such as oxidative stress, accumulation of autoxidative lipofuscin in the lysosomes of retinal pigmented epithelial (RPE) cells [9,10,11,12,13,14] and accumulation of drusen in between Bruch’s membrane and the epithelial layer [15,16] affect the RPE which results in the senescence of these cells. The role of alternative splicing in the pathogenesis of AMD is not well understood
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