COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

中文翻译：

---

SARS-CoV-2感染导致多巴胺能神经元衰老

COVID-19 患者通常出现中枢神经系统和/或周围神经系统功能障碍的体征。在这里，我们发现源自人类多能干细胞（hPSC）的中脑多巴胺（DA）神经元选择性地易感并允许严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染。DA 神经元的 SARS-CoV-2 感染会引发炎症和细胞衰老反应。对 hPSC 衍生的 DA 神经元进行高通量筛选，发现了几种 FDA 批准的药物，可以通过预防 SARS-CoV-2 感染来挽救细胞衰老表型。我们还确定了 COVID-19 患者的人类黑质组织中的炎症和细胞衰老特征以及低水平的 SARS-CoV-2 转录本。此外，我们观察到一组重症 COVID-19 患者中神经黑色素+和酪氨酸羟化酶 (TH)+ DA 神经元和纤维的数量减少。我们的研究结果表明，hPSC 衍生的 DA 神经元对 SARS-CoV-2 敏感，确定了针对 COVID-19 患者的候选神经保护药物，并表明需要对 COVID-19 患者的神经系统问题进行仔细、长期的监测。