In the wake of the ongoing COVID-19 pandemic, scientists and medical professionals continue to uncover a myriad of complications associated with the SARS-CoV-2 virus, extending beyond the typical respiratory symptoms. Among these complications are neurological manifestations that range from mild symptoms like anosmia and dysgeusia to more severe conditions such as seizures, stroke, and acute inflammatory polyradiculoneuropathy, also known as Guillain-Barre syndrome. These neurological effects have garnered increasing attention, prompting researchers to delve into the complex relationship between SARS-CoV-2 and the nervous system.
Recent studies have focused on understanding the virus’s ability to infect various types of neurons within the central nervous system (CNS). While some evidence suggests that certain neural cells, like choroid plexus cells, are highly susceptible to SARS-CoV-2 infection, the virus’s tropism for neurons has remained a subject of controversy. To shed light on this matter, scientists have employed human pluripotent stem cell (hPSC)-derived organoid models, revealing that not all neuronal populations are equally permissive to the virus.
One notable finding is that hPSC-derived midbrain dopamine (DA) neurons, which are critical in Parkinson’s disease (PD), have been identified as susceptible to SARS-CoV-2 infection. In contrast, hPSC-derived cortical neurons did not exhibit permissiveness to the virus. This observation underscores the specificity of the virus’s interaction with different neuronal subtypes.
In a recent study, researchers sought to elucidate the response of DA neurons to SARS-CoV-2 infection and explore the molecular changes induced by the virus. To achieve this, they utilized a differentiated DA neuron model from hPSCs and confirmed that these neurons can indeed be infected by SARS-CoV-2. The study further emphasized that DA neurons with an A9-like subtype identity, resembling those most affected in PD, may be particularly vulnerable to SARS-CoV-2 infection.
One significant outcome of the research was the revelation that SARS-CoV-2 infection triggers cellular senescence in DA neurons. This finding is of particular interest because senescence of DA neurons has been implicated as a contributing factor in PD pathogenesis. Furthermore, dysfunction in DA neurons has been linked to symptoms such as lethargy and anhedonia, raising questions about their role in the post-COVID lethargy syndrome or long COVID.
Interestingly, the study also highlighted variations in susceptibility to SARS-CoV-2 infection among different DA neurons. For instance, DA neurons derived from induced pluripotent stem cells (iPSCs) with an increased copy number of the SNCA gene exhibited heightened susceptibility to the virus. This observation suggested potential synergistic effects between SARS-CoV-2 infection and genetic mutations associated with PD, such as those involving SNCA.
The research did not stop at identifying the vulnerability of DA neurons but also explored potential therapeutic interventions. Three FDA-approved drugs—riluzole, metformin, and imatinib—were found to mitigate SARS-CoV-2-induced senescence in DA neurons, possibly through inhibiting viral infection. These findings open the door to new treatment avenues and further investigations into the mechanisms behind these drugs’ antiviral activities.
While the study presents valuable insights into the relationship between SARS-CoV-2 and DA neurons, it is not without limitations. The detection of the virus in brain autopsy samples remains contentious, and further studies are required to confirm the findings and rule out technical challenges. Additionally, the study is based on a limited cohort of patients from the early stages of the pandemic, necessitating further research on more recent cases.
In conclusion, the research highlights the susceptibility of DA neurons to SARS-CoV-2 infection and the potential repercussions on cellular senescence and PD-related symptoms. This novel understanding of the virus’s impact on the nervous system underscores the importance of monitoring COVID-19 patients for the development of neurological complications, emphasizing the need for ongoing research in this critical area.
reference link: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00442-3