Dysfunctional one-carbon metabolism identifies vitamins B₆, B₉, B₁₂, and choline as neuroprotective in glaucoma.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-05-20 Epub Date: 2025-05-08 DOI:10.1016/j.xcrm.2025.102127

James R Tribble, Vickie H Y Wong, Kelsey V Stuart, Glyn Chidlow, Alan Nicol, Anne Rombaut, Alessandro Rabiolo, Anh Hoang, Pei Ying Lee, Carola Rutigliani, Tim J Enz, Alessio Canovai, Emma Lardner, Gustav Stålhammar, Christine T O Nguyen, David F Garway-Heath, Robert J Casson, Anthony P Khawaja, Bang V Bui, Pete A Williams

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引用次数: 0

Abstract

Glaucoma, characterized by the loss of retinal ganglion cells (RGCs), is a leading cause of blindness for which there are no neuroprotective therapies. To explore observations of elevated homocysteine in glaucoma, we elevate vitreous homocysteine, which increases RGC death by 6% following ocular hypertension. Genetic association with higher homocysteine does not affect glaucoma-associated outcomes from the UK Biobank and serum homocysteine levels have no effect on glaucomatous visual field progression. This supports a hypothesis in which elevated homocysteine is a pathogenic, rather than causative, feature of glaucoma. Further exploration of homocysteine metabolism in glaucoma animal models demonstrates early and sustained dysregulation of genes involved in one-carbon metabolism and the interaction of essential cofactors and precursors (B₆, B₉, B₁₂, and choline) in whole retina and optic nerve head and RGCs. Supplementing these provides neuroprotection in an acute model and prevents neurodegeneration and protects visual function in a chronic model of glaucoma.

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单碳代谢功能失调表明维生素B6、B9、B12和胆碱在青光眼中具有神经保护作用。

青光眼以视网膜神经节细胞（RGCs）的丧失为特征，是导致失明的主要原因，目前尚无神经保护疗法。为了探讨青光眼中同型半胱氨酸升高的观察结果，我们提高了玻璃体同型半胱氨酸，这使高眼压患者的RGC死亡率增加了6%。高同型半胱氨酸的遗传关联不影响英国生物银行的青光眼相关结果，血清同型半胱氨酸水平对青光眼视野进展没有影响。这支持了一种假设，即升高的同型半胱氨酸是青光眼的致病特征，而不是致病特征。青光眼动物模型中同型半胱氨酸代谢的进一步研究表明，在整个视网膜、视神经头和RGCs中，参与单碳代谢的基因以及必需辅助因子和前体（B6、B9、B12和胆碱）的相互作用早期和持续失调。补充这些可在急性模型中提供神经保护，防止慢性模型青光眼的神经变性和保护视觉功能。

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

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.