Wang Sha-Sha, Yuan Ruo-Lan, Wang Wen-Fei, Peng Ye, Hu Kai-Chao, He Wen-Bin, Zhao Ya-Xian, Yan Xu, Zhang Zhao, Chu Shi-Feng, Chen Nai-Hong
Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
J Adv Res. 2025 Aug 7. doi: 10.1016/j.jare.2025.07.060.
Emerging evidence highlights the exacerbation and sustained Parkinson's disease (PD) progression following COVID-19. The SARS-CoV-2 spike receptor-binding domain (RBD), which can persist in the brain post-infection, is a likely contributor, but how it drives this neuropathology is unclear.
To elucidate the underlying mechanisms of long COVID's impact on PD and identify mechanism that contribute to the continuous progression of PD.
The SARS-CoV-2 spike RBD was stereotactically injected into the substantia nigra pars compacta of α-synuclein (αSyn) A53T mice within a chronic stress-genetic susceptibility model. We characterized the pathological impact of RBD using motor and non-motor behavioral tests, fMRI-based functional connectivity, in vivo electrophysiology, immunofluorescence, and αSyn aggregate analysis. To elucidate the underlying mechanisms, we then employed RNA-sequencing, transmission electron microscopy, microglial depletion, and comparative studies in αSyn A53T mice lacking RTP801 (αSyn A53T; RTP801).
RBD accelerated PD-related motor and non-motor symptom deterioration, impaired brain functional connectivity, and reduced neuronal excitability. It exacerbated dopaminergic neuron degeneration and αSyn aggregation. RTP801 was identified as a critical mediator of RBD-induced PD progression, with its sustained upregulation in dopaminergic neurons dependent on microglial activation. Mechanistically, initially activates microglia induced an increase in neuronal RTP801 via IL-6 and IL-8. RBD leaded to mitochondrial dysfunction, mtDNA release, and activation of the cGAS-STING pathway between neurons and microglia, triggering a mtDNA-cGAS-STING-IFNβ/RTP801 feedback loop, driving neurodegeneration.
Our findings demonstrate that SARS-CoV-2 RBD exacerbates PD progression through a pathogenic crosstalk between microglia and neurons. This neurotoxic signaling is mediated by a mitochondrial mtDNA-cGAS-STING-IFNβ/RTP801 axis. Targeting RTP801 or the STING pathway may therefore represent a promising therapeutic strategy to mitigate long COVID-associated progression of PD.
新出现的证据突显了新型冠状病毒肺炎（COVID-19）后帕金森病（PD）的恶化和疾病持续进展。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突受体结合域（RBD）在感染后可在脑中持续存在，可能是一个促成因素，但它如何引发这种神经病理学尚不清楚。
阐明长期新冠对帕金森病影响的潜在机制，并确定导致帕金森病持续进展的机制。
在慢性应激-遗传易感性模型中，将SARS-CoV-2刺突RBD立体定向注射到α-突触核蛋白（αSyn）A53T小鼠的黑质致密部。我们使用运动和非运动行为测试、基于功能磁共振成像（fMRI）的功能连接、体内电生理学、免疫荧光和αSyn聚集体分析来表征RBD的病理影响。为了阐明潜在机制，我们随后采用了RNA测序、透射电子显微镜、小胶质细胞清除以及在缺乏RTP801的αSyn A53T小鼠（αSyn A53T；RTP801）中的比较研究。
RBD加速了与PD相关的运动和非运动症状恶化，损害了脑功能连接，并降低了神经元兴奋性。它加剧了多巴胺能神经元变性和αSyn聚集。RTP801被确定为RBD诱导的PD进展的关键介质，其在多巴胺能神经元中的持续上调依赖于小胶质细胞激活。从机制上讲，最初激活的小胶质细胞通过白细胞介素-6（IL-6）和白细胞介素-8（IL-8）诱导神经元RTP801增加。RBD导致线粒体功能障碍、线粒体DNA（mtDNA）释放以及神经元和小胶质细胞之间的环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）途径激活，触发mtDNA-cGAS-STING-干扰素β（IFNβ）/RTP801反馈回路，驱动神经退行性变。
我们的研究结果表明，SARS-CoV-2 RBD通过小胶质细胞和神经元之间的致病性串扰加剧了PD进展。这种神经毒性信号由线粒体mtDNA-cGAS-STING-IFNβ/RTP801轴介导。因此，靶向RTP801或STING途径可能是减轻长期新冠相关帕金森病进展的一种有前景的治疗策略。
