回收者的回收:溶酶体成为治疗视网膜变性的新药理靶点。

Autophagy Pub Date : 2024-11-01 Epub Date: 2024-08-17 DOI:10.1080/15548627.2024.2391726
Juan Ignacio Jiménez-Loygorri, Patricia Boya
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引用次数: 0

摘要

大自噬/自噬失调是衰老的标志之一,也与几种老年相关疾病(如老年性黄斑变性(AMD))的高发病率有关。受老年黄斑变性影响的主要细胞类型是视网膜色素上皮(RPE),这种疾病会导致中心视力丧失。尽管在 45-85 岁的人群中,约有 8.7% 的人患有这种疾病,但其发病机理仍然不明。在我们最近的手稿中,我们使用药理碘酸钠(SI)模型来研究老年性黄斑病变,发现 RPE 中存在严重的溶酶体膜通透性(LMP),这会导致自噬通路受阻和蛋白稳态缺陷。使用天然化合物尿石素 A(UA)治疗可减少 RPE 细胞死亡,缓解视力丧失,同时自噬功能也得到了完全恢复。虽然 UA 最初被描述为一种特异性有丝分裂诱导剂,但我们现在发现它还能在溶酶体损伤和 LMP 的情况下促进 SQSTM1/p62 依赖性溶酶体吞噬。基因下调 SQSTM1/p62 能完全消除 UA 对溶酶吞噬的影响,而对有丝分裂的刺激则不受影响。总之,这些发现凸显了尿崩症调节的广泛途径及其在治疗老年性黄斑变性和其他涉及溶酶体损伤的疾病中的应用潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Recycling the recyclers: lysophagy emerges as a new pharmacological target for retinal degeneration.

Dysregulated macroautophagy/autophagy is one of the hallmarks of aging and has also been linked to higher incidence of several age-associated diseases such as age-related macular degeneration (AMD). The main cell type affected in AMD is the retinal pigment epithelium (RPE), and this disease can lead to central vision loss. Despite affecting around 8.7% of the population between 45-85 years, its etiopathogenesis remains unknown. In our recent manuscript using the pharmacological sodium iodate (SI) model of AMD we identified severe lysosomal membrane permeabilization (LMP) in the RPE, that leads to autophagy flux blockage and proteostasis defects. Treatment with the natural compound urolithin A (UA) reduces RPE cell death and alleviates vision loss, concurrent with full autophagy restoration. While UA was initially described as a specific mitophagy inducer, we now show that it is also able to promote SQSTM1/p62-dependent lysophagy in the context of lysosomal damage and LMP. Genetic downregulation of SQSTM1/p62 fully abolishes the effect of UA on lysophagy while mitophagy stimulation remains unaffected. In summary, these findings highlight the wide range of pathways modulated by UA and its potential implementation in the management of AMD and other diseases involving lysosomal damage.

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