SARS-CoV-2 infection causes dopaminergic neuron senescence

• Published in: Cell stem cell Vol. 31; no. 2; p. 196
• Main Authors: Yang, Liuliu, Kim, Tae Wan, Han, Yuling, Nair, Manoj S, Harschnitz, Oliver, Zhu, Jiajun, Wang, Pengfei, Koo, So Yeon, Lacko, Lauretta A, Chandar, Vasuretha, Bram, Yaron, Zhang, Tuo, Zhang, Wei, He, Feng, Pan, Chendong, Wu, Junjie, Huang, Yaoxing, Evans, Todd, van der Valk, Paul, Titulaer, Maarten J, Spoor, Jochem K H, Furler O'Brien, Robert L, Bugiani, Marianna, D J Van de Berg, Wilma, Schwartz, Robert E, Ho, David D, Studer, Lorenz, Chen, Shuibing
• Format: Journal Article
• Language: English
• Published: United States 01-02-2024
• Subjects: Central Nervous System; COVID-19; Dopaminergic Neurons; Humans; Pluripotent Stem Cells; SARS-CoV-2; senescence; SARS-CoV-2; human pluripotent stem cells; dopaminergic neuron
• ISSN: 1875-9777
• DOI: 10.1016/j.stem.2023.12.012

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.