High Temperature Requirement A 1 (HTRA1) Causes Photoreceptor Cell Death in Zebrafish Disease Models.

In this study, we show that the expression of HTRA1 in PRCs, as well as in RPE, is increased by the disease-associated HTRA1 mutation and aging. TUNEL assay and quantitative PCR of apoptosis-associated caspases confirmed that PRC-specific overexpression of HTRA1 induced PRC death. Transgenic zebrafish overexpressing human HTRA1 in rod PRCs showed morphological changes of the RPE, including PRC death and lipofuscin accumulation, features similar to those of early AMD. htra1 expression was also increased in a retinitis pigmentosa zebrafish model compared with wild-type. In both fish lines, PRC death was rescued by the suppression of htra1 by the inhibitor 6-boroV. AKT-FOXO3 signaling downstream of HTRA1 was activated via a tumor growth factor β signal, resulting in PRC death. These findings suggest that HTRA1 derived from PRCs is associated with early AMD via PRC death. HTRA1 is a potentially effective target for neuroprotective therapy of early AMD and other degenerative diseases of PRCs. PMID: 30273602 [PubMed - as supplied by publisher]
Source: Am J Pathol - Category: Pathology Authors: Tags: Am J Pathol Source Type: research