Abca4, mutated in Stargardt disease, is required for structural integrity of cone outer segments.

IF 4 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-01-01 Epub Date: 2025-01-10 DOI:10.1242/dmm.052052
John J Willoughby, Abbie M Jensen
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引用次数: 0

Abstract

Stargardt disease (STGD), the leading cause of inherited childhood blindness, is primarily caused by mutations in the ABCA4 gene; yet, the underlying mechanisms of photoreceptor degeneration remain elusive, partly due to limitations in existing animal disease models. To expand our understanding, we mutated the human ABCA4 paralogues abca4a and abca4b in zebrafish, which has a cone-rich retina. Our study unveiled striking dysmorphology and elongation of cone outer segments (COS) in abca4a;abca4b double mutants, alongside reduced phagocytosis by the retinal pigmented epithelium (RPE). We report that zebrafish Abca4 protein forms a distinctive stripe along the length of COS, suggesting a potential structural role. We further show that, in wild-type zebrafish, outer segments of cone cells constitutively present externalized phosphatidylserine, an apoptotic 'eat-me' signal, and that this pattern is disrupted in abca4a;abca4b double mutants, potentially contributing to reduced RPE phagocytic activity. More broadly, constitutive presentation of the 'eat-me' signal by COS - if conserved in humans - might have important implications for other retinal degenerative diseases, including age-related macular degeneration. Our zebrafish model provides novel insights into cone dysfunction and presents a promising platform for unraveling the mechanisms of STGD pathogenesis and advancing therapeutic interventions.

在Stargardt病中突变的Abca4是圆锥体外节结构完整性所必需的。
Stargardt病(STGD)是遗传性儿童失明的主要原因,主要由ABCA4基因突变引起,但光感受器变性的潜在机制仍然难以捉摸,部分原因是现有动物疾病模型的局限性。为了扩大我们的理解,我们在斑马鱼中突变了ABCA4的类似物,abca4a和abca4b,斑马鱼的视网膜有丰富的锥体。我们的研究揭示了abca4a和abca4b双突变体的显著畸变和锥体外段的伸长,同时视网膜色素上皮的吞噬作用减少。我们报道Abca4蛋白沿着圆锥体外段的长度形成独特的条纹,表明潜在的结构作用。我们进一步表明,野生型锥体外段组成性地呈现外化磷脂酰丝氨酸,这是一种“吃我”信号,这种模式在abca4a和abca4b双突变体中被破坏,可能导致RPE吞噬活性降低。更广泛地说,“吃我”信号在锥体外节的构成表现,如果在人类中保守,对其他视网膜退行性疾病,包括年龄相关性黄斑变性,具有重要意义。该斑马鱼模型提供了对视锥细胞功能障碍的新见解,并为揭示STGD发病机制和推进治疗干预提供了一个有希望的平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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