Eyeing up the role of <i>HTRA1</i> in age-related macular degeneration

Age-related macular degeneration (AMD) is a serious eye disease that leads to deterioration of the retina and causes vision loss. It is a genetically complex disease, and while some risk genes have been identified, in many cases it is not clear how these genes contribute to AMD progression. One such gene linked to AMD is HTRA1, which encodes an enzyme that cleaves other proteins and has been associated with vascular problems in the brain. Some work has suggested that HTRA1 could be modulated therapeutically to treat AMD; however, the exact effects this might have remain unclear.To address this, Katschke, van Lookeren Campagne, Jeanne and colleagues investigated the role of HTRA1 in samples from patients with AMD and mouse models. Immunohistochemistry in healthy donor eye tissue showed that HTRA1 protein was present in the basement membrane that supports the retina and expressed at low levels around the light-detecting photoreceptor cells. Conversely, in samples from patients with AMD, HTRA1 was found in the membranous, collagen-rich deposits characteristic of AMD and accumulated at higher levels around the photoreceptors. To assess whether HTRA1 drives AMD, the authors generated transgenic mouse models overexpressing either a functional or enzymatically inactive version of HTRA1 in the layer of epithelial cells supporting the retina. Overexpression of functional HTRA1 caused decreased retinal thickness and photoreceptor degeneration, reflecting AMD pathology. This was not observed in the absence of HTRA1’s enzymatic activity, suggesting that degeneration is driven by HTRA1’s function. The authors also tested whether HTRA1 activity impacted the retina’s ability to recover from laser-induced damage, which mimics blood vessel invasion often seen in later stages of AMD. These lesions grew larger in the presence of overexpressed HTRA1, suggesting that its activity promotes vascular growth in the retina. Finally, they investigated the pathways through which HTRA1’s enzymatic activity could contribute to accelerating AMD. They performed immunoprecipitation experiments to find proteins that interact with functional HTRA1 and could therefore be targets of the enzyme. One protein identified was RBP3, which is secreted by photoreceptors and essential for vertebrate vision. They showed that RBP3 is indeed cleaved by HTRA1, suggesting that HTRA1 activity could promote AMD progression by causing excessive breakdown of an important vision protein, RBP3.Altogether, this work provides new insights into the pathogenesis of AMD with improved mechanistic understanding of a disease risk gene. This understanding is crucial to assess how modulating risk genes could help or hinder treatment strategies.DMM Research or Resources & Methods articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.