SARS-CoV-2 infection causes dopaminergic neuron senescence

被引：42

作者：

Yang, Liuliu ^{[1
,2
]}

Kim, Tae Wan ^{[3
,4
,5
]}

Han, Yuling ^{[1
,2
]}

Nair, Manoj S. ^{[6
]}

Harschnitz, Oliver ^{[7
]}

Zhu, Jiajun ^{[1
,2
]}

Wang, Pengfei ^{[6
]}

Koo, So Yeon ^{[3
,4
,5
,8
]}

Lacko, Lauretta A. ^{[1
,2
]}

Chandar, Vasuretha ^{[9
,10
]}

Bram, Yaron ^{[9
,10
]}

Zhang, Tuo ^{[11
]}

Zhang, Wei ^{[10
]}

He, Feng ^{[11
]}

Pan, Chendong ^{[11
]}

Wu, Junjie ^{[1
,2
]}

Huang, Yaoxing ^{[6
]}

Evans, Todd ^{[1
,2
]}

van der Valk, Paul ^{[12
]}

Titulaer, Maarten J. ^{[13
]}

Spoor, Jochem K. H. ^{[14
]}

O'Brien, Robert L. Furler ^{[15
]}

Buglani, Marianna ^{[16
,17
]}

Van de Berg, Wilma D. J. ^{[17
,18
]}

Schwartz, Robert E. ^{[9
,10
]}

Ho, David D. ^{[6
]}

Studer, Lorenz ^{[3
,4
,5
]}

Chen, Shuibing ^{[1
,2
]}

机构：

[1] Dept Surg, Weill Cornell Med, 1300 York Ave, New York, NY 10065 USA

[2] Ctr Genom Hlth, Weill Cornell Med, 1300 York Ave, New York, NY 10065 USA

[3] Sloan Kettering Inst Canc Res, Ctr Stem Cell Biol, New York, NY 10065 USA

[4] Sloan Kettering Inst Canc Res, Dev Biol Program, New York, NY 10065 USA

[5] Aligning Sci Parkinsons ASAP Collaborat Res Networ, Chevy Chase, MD 20815 USA

[6] Columbia Univ, Vagelos Coll Phys & Surg, Aaron Diamond AIDS Res Ctr, New York, NY 10032 USA

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

[8] Weill Cornell Grad Sch Biomed Sci, Neurosci Grad Program, New York, NY USA

[9] Weill Cornell Med, Dept Med, Div Gastroenterol & Hepatol, 1300 York Ave, New York, NY 10065 USA

[10] Weill Cornell Med, Dept Physiol Biophys & Syst Biol, 1300 York Ave, New York, NY 10065 USA

[11] Genom Resource Core Facil, Weill Cornell Med, New York, NY 10065 USA

[12] Vrije Univ Amsterdam, Amsterdam Univ, Med Ctr, Dept Pathol, Amsterdam, Netherlands

[13] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[14] Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands

[15] Dept Med, Div Infect Dis, Weill Cornell Med, 1300 York Ave, New York, NY 10065 USA

[16] Locat Vrije Univ Amsterdam, Dept Pathol, Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands

[17] Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands

[18] Locat Vrije Univ Amsterdam, Dept Anat & Neurosci, Sect Clin Neuroanat & Biobanking, Amsterdam UMC, De Boelelaan 1117, Amsterdam, Netherlands

来源：

CELL STEM CELL | 2024年 / 31卷 / 02期

关键词：

ALPHA-SYNUCLEIN; CHOROID-PLEXUS; LEWY BODY; COVID-19; CELLS; GENE;

D O I：

10.1016/j.stem.2023.12.012

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 FDAapproved 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.

引用

页码：196 / 211.e6

页数：23

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