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SARS-CoV-2 Infection Causes Dopaminergic Neuron Senescence.
- Source :
-
Research square [Res Sq] 2021 May 21. Date of Electronic Publication: 2021 May 21. - Publication Year :
- 2021
-
Abstract
- COVID-19 patients commonly present with neurological signs of central nervous system (CNS) <superscript>1-3</superscript> and/or peripheral nervous system dysfunction <superscript>4</superscript> . However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo , and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.<br />Competing Interests: Competing Interests. R.E.S. is on the scientific advisory board of Miromatrix Inc and is a paid consultant and speaker for Alnylam Inc. L.S. is a scientific cofounder and paid consultant of BlueRock Therapeutics Inc. The other authors declare no competing interests.
Details
- Language :
- English
- Database :
- MEDLINE
- Journal :
- Research square
- Accession number :
- 34031650
- Full Text :
- https://doi.org/10.21203/rs.3.rs-513461/v1