Khan Sazzad, Delotterie David F, Xiao Jianfeng, Thangavel Ramasamy, Hori Roderick, Koprich James, Alway Stephen E, McDonald Michael P, Khan Mohammad Moshahid
Department of Neurology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Brain Behav Immun. 2025 Jul 31:106065. doi: 10.1016/j.bbi.2025.106065.
Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by substantial degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum, leading to debilitating motor and non-motor impairments. Recent studies provide clues on the pathogenic role of DNA damage in age-related neurodegenerative diseases, but the molecular mechanisms of DNA damage response in PD remain poorly understood. We found that the accumulation of DNA double-strand breaks (DDSBs), and/or DNA repair deficits, are key in the pathogenesis of PD and drives cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) immune regulatory pathway, contributing to neuroinflammation and dopaminergic neurodegeneration in human postmortem PD and non-PD brains as well as in experimental models of PD. We observed enhanced expression of γ-H2A.X (Ser139) a biomarker of DDSB, and decreased levels of DNA repair proteins in the brains of human PD compared to non-PD brains. This was positively correlated with upregulation of STING immune response pathways, microglial activation, senescence and dopaminergic neurodegeneration. Similarly, we observed increased and sustained DDSB as assessed by γ-H2A.X (Ser139) immunoreactivity, and degeneration of tyrosine hydroxylase-positive neurons in primary neuron/glia cultures and mice treated with 1-methyl-4-phenylpyridine (MPP+) or 1,2,3,6-tetrahydropyridine (MPTP). Next, we employed a mouse model of α-synucleinopathy, which exhibited elevated DDSBs alongside overactivation of the DNA-sensing cGAS-STING pathway and type-I interferon signaling, in association with dopaminergic neurodegeneration. Interestingly, pharmacological and genetic ablation of STING reduces DDSB, limits inflammatory response, improves behavioral function and attenuates the loss of dopaminergic neurons in this model. Our findings suggest that the accumulation of DDSBs and/or dysregulation in DNA repair proteins activate cGAS-STING mediated immune responses in the brain, potentially exacerbating dopaminergic neurodegeneration in PD. Furthermore, regulating these processes is essential for alleviating the pathological effects of PD and may offer potential therapeutic strategies.
帕金森病（PD）是一种进行性神经退行性疾病，其特征是黑质中多巴胺能神经元大量退化以及纹状体中多巴胺耗竭，导致使人衰弱的运动和非运动障碍。最近的研究为DNA损伤在年龄相关性神经退行性疾病中的致病作用提供了线索，但PD中DNA损伤反应的分子机制仍知之甚少。我们发现，DNA双链断裂（DDSBs）的积累和/或DNA修复缺陷是PD发病机制的关键，并驱动环磷酸鸟苷-腺苷酸合成酶（cGAS）和干扰素基因刺激物（STING）免疫调节途径，导致人类帕金森病和非帕金森病死后大脑以及帕金森病实验模型中的神经炎症和多巴胺能神经变性。与非帕金森病大脑相比，我们观察到人类帕金森病大脑中DDSB的生物标志物γ-H2A.X（Ser139）表达增强，DNA修复蛋白水平降低。这与STING免疫反应途径的上调、小胶质细胞活化、衰老和多巴胺能神经变性呈正相关。同样，通过γ-H2A.X（Ser139）免疫反应性评估，我们观察到原代神经元/神经胶质细胞培养物和用1-甲基-4-苯基吡啶（MPP+）或1,2,3,6-四氢吡啶（MPTP）处理的小鼠中DDSB增加且持续存在，以及酪氨酸羟化酶阳性神经元变性。接下来，我们采用了一种α-突触核蛋白病小鼠模型，该模型表现出DDSBs升高，同时DNA传感cGAS-STING途径和I型干扰素信号过度激活，并伴有多巴胺能神经变性。有趣的是，在该模型中，STING的药理学和基因消融可减少DDSB，限制炎症反应，改善行为功能并减轻多巴胺能神经元的损失。我们的研究结果表明，DDSBs的积累和/或DNA修复蛋白的失调激活了大脑中cGAS-STING介导的免疫反应，可能会加剧PD中的多巴胺能神经变性。此外，调节这些过程对于减轻PD的病理影响至关重要，并可能提供潜在的治疗策略。
