SARS-CoV-2 infection causes dopaminergic neuron senescence

The study “SARS-CoV-2 infection causes dopaminergic neuron senescence” provides critical insights into the impact of COVID-19 on the nervous system, especially regarding dopaminergic (DA) neurons, which are crucial for motor control and reward systems.

Here’s a detailed summary:

Study Overview:

  • Objective: To understand how SARS-CoV-2 affects midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs).
  • Key Findings: The study demonstrates that hPSC-derived DA neurons are susceptible to SARS-CoV-2 infection, leading to an inflammatory and cellular senescence response. Additionally, the study explores FDA-approved drugs that can mitigate these effects and observes related pathologies in the substantia nigra tissue of COVID-19 patients​​.

Key Insights and Findings:

  1. SARS-CoV-2 Induced Senescence in DA Neurons: SARS-CoV-2 infection in hPSC-derived DA neurons was found to induce cellular senescence, evidenced by the upregulation of pathways related to the cell cycle, DNA replication, and senescence. This was further supported by the increased expression of chemokine/cytokine transcripts, inflammation-related genes, and senescence-associated genes. Notably, this senescence pathway was not significantly enriched in SARS-CoV-2 infected organoids from other organs such as the lungs, pancreas, liver, and heart​​.
  2. Activation of Senescence-Associated Secretory Phenotype (SASP): The study observed upregulation of SASP-associated genes and markers in SARS-CoV-2 infected DA neurons, indicating the activation of SASP. This includes an increase in acidic lysosomal senescence-associated b-galactosidase activity, lipofuscin accumulation, and increased nuclear size. These findings point towards an accelerated senescence process in DA neurons upon SARS-CoV-2 infection​​.
  3. Identification of Neuroprotective Drugs: High-throughput screening identified several FDA-approved drugs that could potentially protect DA neurons from SARS-CoV-2 induced senescence. Riluzole, metformin, and imatinib were among the drugs that showed a significant reduction in the senescence markers in DA neurons. These drugs decreased lysosomal accumulation and altered the expression of genes associated with the senescence pathway. This finding opens new avenues for potential therapeutic interventions to protect neuronal health in COVID-19 patients​​.

Conclusions and Implications: The study highlights the vulnerability of DA neurons to SARS-CoV-2 and the resultant cellular senescence, shedding light on the potential neurological complications in COVID-19 patients. The identification of FDA-approved drugs that can mitigate these effects emphasizes the possibility of repurposing existing drugs to manage neurodegenerative symptoms in COVID-19 patients. However, further research and clinical trials are necessary to confirm the efficacy and safety of these drugs in the context of COVID-19 related neurological issues.

Read More: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00442-3

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