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Sloan-Kettering Institute for Cancer Research, 현 DGIST

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Cell Stem Cell, Jan 10 2024, S1934-5909(23)00442-3 | https://doi.org/10.1016/j.stem.2023.12.012 SARS-CoV-2 infection causes dopaminergic neuron senescence

Liuliu Yang ^1,2,19, Tae Wan Kim ^3,4,5,19, Yuling Han ^1,2,19, Manoj S. Nair ^6,19, Oliver Harschnitz^7,19, Jiajun Zhu ^1,2,19, Pengfei Wang ^6,19, So Yeon Koo ^3,4,5,8, Lauretta A. Lacko ^1,2, Vasuretha Chandar ^9,10, Yaron Bram ^9,10, Tuo Zhang ¹¹, Wei Zhang ¹⁰, Feng He ¹¹, Chendong Pan¹¹, Junjie Wu ^1,2, Yaoxing Huang ⁶, Todd Evans ^1,2, Paul van der Valk ¹², Maarten J. Titulaer ¹³, Jochem K.H. Spoor ¹⁴, Robert L. Furler O’Brien ¹⁵, Marianna Bugiani ^16,17, Wilma D.J. Van de Berg ^17,18, Robert E. Schwartz ^9,10, David D. Ho ⁶, Lorenz Studer ^3,4,5, Shuibing Chen^1,2,20

¹Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA

²Center for Genomic Health, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA

³The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA

⁴Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA

⁵Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA

⁶Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA

⁷Human Technopole, Viale Rita Levi-Montalcini, 1, 20157 Milan, Italy

⁸Neuroscience Graduate Program of Weill Cornell Graduate School of Biomedical Sciences, New York, NY, USA

⁹Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA

¹⁰Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA

¹¹Genomic Resource Core Facility, Weill Cornell Medicine, New York, NY 10065, USA

¹²Department of Pathology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, the Netherlands

¹³Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands

¹⁴Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, the Netherlands

¹⁵Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA

¹⁶Amsterdam UMC, Location Vrije Universiteit Amsterdam, Department of Pathology, De Boelelaan 1117, Amsterdam, the Netherlands

¹⁷Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands

¹⁸Amsterdam UMC, Location Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, De Boelelaan 1117, Amsterdam, the Netherlands

¹⁹These authors contributed equally

²⁰Lead contact

Corresponding authors: Robert E. Schwartz, David D. Ho, Lorenz Studer, Shuibing Chen

Abstract

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-29)
연구진국외 연구진
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