SARS-CoV-2 infection causes dopaminergic neuron senescence

Liuliu Yang; Tae Wan Kim; Yuling Han; Manoj S. Nair; Oliver Harschnitz; Jiajun Zhu; Pengfei Wang; So Yeon Koo; Lauretta A. Lacko; Vasuretha Chandar; Yaron Bram; Tuo Zhang; Wei Zhang; Feng He; Chendong Pan; Junjie Wu; Yaoxing Huang; Todd Evans; Paul van der Valk; Maarten J. Titulaer; Jochem K.H. Spoor; Robert L. Furler O'Brien; Marianna Bugiani; Wilma D.J. Van de Berg; Robert E. Schwartz; David D. Ho; Lorenz Studer; Shuibing Chen

doi:10.1016/j.stem.2023.12.012

SARS-CoV-2 infection causes dopaminergic neuron senescence

Liuliu Yang, Tae Wan Kim, Yuling Han, Manoj S. Nair, Oliver Harschnitz, Jiajun Zhu, Pengfei Wang, So Yeon Koo, Lauretta A. Lacko, Vasuretha Chandar, Yaron Bram, Tuo Zhang, Wei Zhang, Feng He, Chendong Pan, Junjie Wu, Yaoxing Huang, Todd Evans, Paul van der Valk, Maarten J. TitulaerJochem K.H. Spoor, Robert L. Furler O'Brien, Marianna Bugiani, Wilma D.J. Van de Berg, Robert E. Schwartz^*, David D. Ho^*, Lorenz Studer^*, Shuibing Chen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	196-211.e6
Journal	Cell Stem Cell
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2023.12.012
Publication status	Published - 1 Feb 2024

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© 2023 The Author(s)

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Yang, L., Kim, T. W., Han, Y., Nair, M. S., Harschnitz, O., Zhu, J., Wang, P., Koo, S. Y., Lacko, L. A., Chandar, V., Bram, Y., Zhang, T., Zhang, W., He, F., Pan, C., Wu, J., Huang, Y., Evans, T., van der Valk, P., ... Chen, S. (2024). SARS-CoV-2 infection causes dopaminergic neuron senescence. Cell Stem Cell, 31(2), 196-211.e6. https://doi.org/10.1016/j.stem.2023.12.012

@article{ded0086803434c47bdb35513d01c6414,

title = "SARS-CoV-2 infection causes dopaminergic neuron senescence",

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.",

author = "Liuliu Yang and Kim, {Tae Wan} and Yuling Han and Nair, {Manoj S.} and Oliver Harschnitz and Jiajun Zhu and Pengfei Wang and Koo, {So Yeon} and Lacko, {Lauretta A.} and Vasuretha Chandar and Yaron Bram and Tuo Zhang and Wei Zhang and Feng He and Chendong Pan and Junjie Wu and Yaoxing Huang and Todd Evans and {van der Valk}, Paul and Titulaer, {Maarten J.} and Spoor, {Jochem K.H.} and {Furler O'Brien}, {Robert L.} and Marianna Bugiani and {D.J. Van de Berg}, Wilma and Schwartz, {Robert E.} and Ho, {David D.} and Lorenz Studer and Shuibing Chen",

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day = "1",

doi = "10.1016/j.stem.2023.12.012",

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Yang, L, Kim, TW, Han, Y, Nair, MS, Harschnitz, O, Zhu, J, Wang, P, Koo, SY, Lacko, LA, Chandar, V, Bram, Y, Zhang, T, Zhang, W, He, F, Pan, C, Wu, J, Huang, Y, Evans, T, van der Valk, P, Titulaer, MJ , Spoor, JKH, Furler O'Brien, RL, Bugiani, M, D.J. Van de Berg, W, Schwartz, RE, Ho, DD, Studer, L & Chen, S 2024, 'SARS-CoV-2 infection causes dopaminergic neuron senescence', Cell Stem Cell, vol. 31, no. 2, pp. 196-211.e6. https://doi.org/10.1016/j.stem.2023.12.012

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AU - Yang, Liuliu

AU - Kim, Tae Wan

AU - Han, Yuling

AU - Nair, Manoj S.

AU - Harschnitz, Oliver

AU - Zhu, Jiajun

AU - Wang, Pengfei

AU - Koo, So Yeon

AU - Lacko, Lauretta A.

AU - Chandar, Vasuretha

AU - Bram, Yaron

AU - Zhang, Tuo

AU - Zhang, Wei

AU - He, Feng

AU - Pan, Chendong

AU - Wu, Junjie

AU - Huang, Yaoxing

AU - Evans, Todd

AU - van der Valk, Paul

AU - Titulaer, Maarten J.

AU - Spoor, Jochem K.H.

AU - Furler O'Brien, Robert L.

AU - Bugiani, Marianna

AU - D.J. Van de Berg, Wilma

AU - Schwartz, Robert E.

AU - Ho, David D.

AU - Studer, Lorenz

AU - Chen, Shuibing

PY - 2024/2/1

Y1 - 2024/2/1

N2 - 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.

AB - 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.

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DO - 10.1016/j.stem.2023.12.012

M3 - Article

C2 - 38237586

AN - SCOPUS:85183491822

SN - 1934-5909

VL - 31

SP - 196-211.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

SARS-CoV-2 infection causes dopaminergic neuron senescence

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