Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen
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引用次数: 0
Abstract
Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to the adult. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Evidence points to increased DNA methylation, especially in degenerating photoreceptors, as a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigates the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (Rho-/-). We observed elevated levels of DNA methyltransferases (DNMTs) and DNA methylation during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in Rho-/- mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histological and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared to controls. Together, these findings reveal that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphological and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.