Marola Olivia J, MacLean Michael, Cossette Travis L, Diemler Cory A, Hewes Amanda A, Reagan Alaina M, Kanyinda Jonathan Nyandu, Skelly Daniel A, Howell Gareth R
The Jackson Laboratory, Bar Harbor, ME, 04609, USA.
Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, 04469, USA.
Mol Neurodegener. 2025 Jan 20;20(1):8. doi: 10.1186/s13024-025-00800-9.
Age is the principal risk factor for neurodegeneration in both the retina and brain. The retina and brain share many biological properties; thus, insights into retinal aging and degeneration may shed light onto similar processes in the brain. Genetic makeup strongly influences susceptibility to age-related retinal disease. However, studies investigating retinal aging have not sufficiently accounted for genetic diversity. Therefore, examining molecular aging in the retina across different genetic backgrounds will enhance our understanding of human-relevant aging and degeneration in both the retina and brain-potentially improving therapeutic approaches to these debilitating conditions.
Transcriptomics and proteomics were employed to elucidate retinal aging signatures in nine genetically diverse mouse strains (C57BL/6J, 129S1/SvlmJ, NZO/HlLtJ, WSB/EiJ, CAST/EiJ, PWK/PhK, NOD/ShiLtJ, A/J, and BALB/cJ) across lifespan. These data predicted human disease-relevant changes in WSB and NZO strains. Accordingly, B6, WSB, and NZO mice were subjected to human-relevant in vivo examinations at 4, 8, 12, and/or 18M, including: slit lamp, fundus imaging, optical coherence tomography, fluorescein angiography, and pattern/full-field electroretinography. Retinal morphology, vascular structure, and cell counts were assessed ex vivo.
We identified common molecular aging signatures across the nine mouse strains, which included genes associated with photoreceptor function and immune activation. Genetic background strongly modulated these aging signatures. Analysis of cell type-specific marker genes predicted age-related loss of photoreceptors and retinal ganglion cells (RGCs) in WSB and NZO, respectively. Fundus exams revealed retinitis pigmentosa-relevant pigmentary abnormalities in WSB retinas and diabetic retinopathy (DR)-relevant cotton wool spots and exudates in NZO retinas. Profound photoreceptor dysfunction and loss were confirmed in WSB. Molecular analyses indicated changes in photoreceptor-specific proteins prior to loss, suggesting photoreceptor-intrinsic dysfunction in WSB. In addition, age-associated RGC dysfunction, loss, and concomitant microvascular dysfunction were observed in NZO mice. Proteomic analyses revealed an early reduction in protective antioxidant processes, which may underlie increased susceptibility to DR-relevant pathology in NZO.
Genetic context is a strong determinant of retinal aging, and our multi-omics resource can aid in understanding age-related diseases of the eye and brain. Our investigations identified and validated WSB and NZO mice as improved preclinical models relevant to common retinal neurodegenerative diseases.
年龄是视网膜和大脑神经退行性变的主要风险因素。视网膜和大脑具有许多生物学特性；因此，对视网膜衰老和退化的深入了解可能有助于揭示大脑中的类似过程。基因组成强烈影响与年龄相关的视网膜疾病的易感性。然而，研究视网膜衰老的研究尚未充分考虑基因多样性。因此，研究不同遗传背景下视网膜的分子衰老将增进我们对视网膜和大脑中与人类相关的衰老和退化的理解，有可能改善针对这些使人衰弱病症的治疗方法。
采用转录组学和蛋白质组学方法，在9种基因不同的小鼠品系（C57BL/6J、129S1/SvlmJ、NZO/HlLtJ、WSB/EiJ、CAST/EiJ、PWK/PhK、NOD/ShiLtJ、A/J和BALB/cJ）的整个生命周期中阐明视网膜衰老特征。这些数据预测了WSB和NZO品系中与人类疾病相关的变化。因此，对B6、WSB和NZO小鼠在4、8、12和/或18月龄时进行了与人类相关的体内检查，包括：裂隙灯检查、眼底成像、光学相干断层扫描、荧光素血管造影以及图形/全视野视网膜电图检查。离体评估视网膜形态、血管结构和细胞计数。
我们在9种小鼠品系中鉴定出了共同的分子衰老特征，其中包括与光感受器功能和免疫激活相关的基因。遗传背景强烈调节这些衰老特征。对细胞类型特异性标记基因的分析分别预测了WSB和NZO中与年龄相关的光感受器和视网膜神经节细胞（RGC）的损失。眼底检查显示，WSB视网膜中存在与色素性视网膜炎相关的色素异常，而NZO视网膜中存在与糖尿病视网膜病变（DR）相关的棉絮斑和渗出物。在WSB中证实了严重的光感受器功能障碍和损失。分子分析表明，在损失之前光感受器特异性蛋白质发生了变化，这表明WSB中存在光感受器内在功能障碍。此外，在NZO小鼠中观察到与年龄相关的RGC功能障碍、损失以及伴随的微血管功能障碍。蛋白质组学分析显示，保护性抗氧化过程早期减少，这可能是NZO对DR相关病理易感性增加的基础。
遗传背景是视网膜衰老的一个重要决定因素，我们的多组学资源有助于理解与年龄相关的眼部和脑部疾病。我们的研究确定并验证了WSB和NZO小鼠是与常见视网膜神经退行性疾病相关的更好的临床前模型。
