A genetic basis for age-related macular degeneration (AMD) has been greatly advanced in recent years. The role of identified pathways such as complement factor H in AMD has been widely investigated. However, the effect of other gene variants identified by genome-wide screens is not so well understood. One such gene is high temperature requirement A1 (HtrA1). HtrA1 encodes a serine protease that has been implicated in protection against cellular stress, and as a tumour suppressor. This study analyses the role of HtrA1 in cell senescence a feature of retinal pigment epithelium (RPE) cells in AMD. Premature senescence was induced in mouse embryonic fibroblasts (MEF) and an RPE cell line (ARPE-19) by treatment with hydrogen peroxide. Expression of senescence markers, such as p16INK4a, were higher in HtrA1 heterozgote MEF compared to deficient cells. HtrA1 WT and heterozygote cells were more resistant to H2O2-induced cell death than deficient cells. Expression of excess HtrA1 led to premature senescence in both MEF and ARPE-19. These results show that HtrA1 is activated by oxidative stress and induces cell senescence as a protective measure. However, chronic stress would lead to an increase in senescent cells in conditions such as AMD driving tissue damage.

HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway.
Supanji, Shimomachi M, Hasan MZ, et al.
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Graham Wallace

Birmingham and Midland Eye Centre, Birmingham, UK.

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