BREAKING COVID-19 News! Italian Study Shows That SARS-CoV-2 Infects Dopaminergic Neurons And Hampers Dopamine Production!

COVID-19 News: The COVID-19 pandemic has posed unprecedented challenges to the global healthcare community, leading to intensive research efforts to comprehend the virus's multifaceted effects on the human body. Beyond its well-known respiratory symptoms, COVID-19 has revealed a puzzling array of neurological complications, ranging from anosmia and ageusia to more severe conditions like encephalitis. As scientists grapple with these neurological mysteries, a groundbreaking study conducted by the University of Milan in Italy and the IRCCS Fondazione Don Gnocchi has unveiled a previously unexplored facet of the virus's impact on the human brain. This study suggests that SARS-CoV-2, the virus responsible for COVID-19, may infect dopaminergic neurons and disrupt dopamine production, potentially shedding light on some of the neurological symptoms experienced by COVID-19 patients.


                                                                                                    Graphical Abstract
 
The Quest for Answers
Since the early stages of the pandemic, it became evident that SARS-CoV-2 had the capability to infiltrate and affect the nervous system. A wide range of neurological symptoms emerged, leaving medical professionals perplexed and prompting intense research into the virus's effects on the brain. These symptoms include anosmia (loss of smell), ageusia (loss of taste), headaches, encephalitis, and more. Notably, these neurological complications are not limited to mild cases; even individuals who have recovered from COVID-19 report persistent symptoms long after their initial diagnosis as reported in numerous studies, case reports and COVID-19 News coverages.
 
Furthermore, emerging evidence has suggested that SARS-CoV-2 has a direct impact on the brain. Studies have revealed a reduction in grey matter thickness, increased tissue damage markers in regions connected to the olfactory cortex, and an overall decrease in brain size following SARS-CoV-2 infection. Additionally, individuals with pre-existing neurological disorders appear to be at a heightened risk of experiencing neurological symptoms upon contracting COVID-19.
 
Amid these findings, researchers have begun to explore whether the virus might affect dopamine production and the dopamine pathway in the brain. Dopamine is a crucial neurotransmitter involved in a wide range of functions, including motor control, mood regulation, and reward processing. If SARS-CoV-2 indeed influences dopamine production, it could potentially explain some of the neurological symptoms observed in COVID-19 patients. However, until now, no scientific evidence had substantiated this hypothesis.
 
The Italia n Study: Unveiling SARS-CoV-2's Effect on Dopamine
To address this crucial question, scientists at the University of Milan and IRCCS Fondazione Don Gnocchi conducted an innovative study. They employed a cutting-edge in vitro model using human induced pluripotent stem cell-derived dopaminergic neurons (DA neurons) infected with three SARS-CoV-2 variants: EU, Delta, and Omicron.
 
The study yielded several compelling results:
 
SARS-CoV-2 Infection of Dopaminergic Neurons: The study began with a characterization of the DA neurons in culture, confirming that 100% of the neurons were dopaminergic, as indicated by the presence of key markers like tyrosine hydroxylase (TH) and MAP2. This validation ensured the suitability of the model for studying dopaminergic function.
 
Next, the DA neurons were exposed to various concentrations of three SARS-CoV-2 variants: EU, Delta, and Omicron. Remarkably, the researchers observed that all three variants were capable of infecting the DA neurons. While the infection did not lead to a significant decrease in cell viability, it did result in a steady increase in viral RNA levels over time.
 
To assess the infectivity of the progeny virus, the researchers collected supernatants from infected DA neurons and tested them on VeroE6 cells. They found that all three SARS-CoV-2 variants had a modest ability to produce infectious progeny virus, suggesting that the virus could replicate within dopaminergic neurons.
 
Neuronal Stress Markers: In addition to viral replication, the researchers also investigated the impact of SARS-CoV-2 infection on innate immunity and neuronal stress markers. The study found that SARS-CoV-2 infection led to an increase in innate immunity and stress markers in DA neurons The study team discovered that infected DA neurons exhibited an upregulation of genes associated with the antiviral response, such as MxA and IFITM3. Furthermore, a neuronal stress marker called S100B was also upregulated, indicating that the virus induced stress in these neurons.
 
Interestingly, this neuronal stress response was not limited to a specific SARS-CoV-2 variant. Both EU and Delta variants triggered this response, suggesting a common feature among these variants in their ability to induce stress in dopaminergic neurons.
 
Dopamine Metabolic Pathway Alterations: Given the clinical observations of COVID-19 patients experiencing dopaminergic-related symptoms, the researchers focused on the dopamine metabolic pathway within the DA neurons. They measured intracellular dopamine content and extracellular release, exploring whether the virus's impact on dopamine production was dependent on the viral variant or the virus dose.
 
The results were striking. Both EU and Delta variants of SARS-CoV-2 significantly reduced dopamine production and secretion, with the degree of reduction varying with the viral dose. Notably, the Omicron variant did not have a significant effect on dopamine production in infected neurons.
 
TH and Dopamine Pathway Proteins: The researchers delved deeper into the dopamine pathway and found that TH, the enzyme responsible for converting tyrosine to DOPA, was markedly reduced at the protein level in DA neurons infected with EU and Delta variants. Additionally, DOPA decarboxylase (DDC) and the dopamine transporter (DAT) exhibited downregulation at both the mRNA and protein levels. These findings indicate a direct impact of SARS-CoV-2 on the dopamine synthesis pathway.
 
Vesicular Monoamine Transporter 2 (VMAT2): VMAT2, another essential component of dopamine metabolism, displayed a modest increase only upon infection with the EU SARS-CoV-2 variant. No significant changes were observed with the Omicron variant.
 
Implications of the Study
The implications of this groundbreaking study are far-reaching. It suggests that SARS-CoV-2 can indeed infect dopaminergic neurons in the human brain, providing a potential explanation for some of the neurological symptoms observed in COVID-19 patients. By disrupting the dopamine metabolic pathway, the virus may contribute to the development of conditions such as anosmia, ageusia, headaches, and even more severe neurological issues.
 
Furthermore, the study highlights the variant-specific effects of SARS-CoV-2 on dopamine production. The EU and Delta variants, which have been associated with more severe cases of COVID-19, demonstrated a greater impact on dopamine metabolism compared to the Omicron variant, which has generally caused milder symptoms. This finding could help explain the differences in neurological symptomatology among COVID-19 patients infected with various virus variants.
 
Implications for Parkinson's Disease
The study also has potential implications for individuals with Parkinson's disease. It is known that patients with pre-existing neurological conditions, such as Parkinson's disease, may experience worsening symptoms during and after COVID-19 infection. The study's findings suggest that SARS-CoV-2-induced disruption of dopamine production in dopaminergic neurons may play a role in these exacerbations of symptoms. However, further research is needed to fully understand this connection and its clinical implications.
 
Conclusion
The Italian study conducted by the University of Milan and IRCCS Fondazione Don Gnocchi marks a significant milestone in our understanding of COVID-19's neurological effects. By demonstrating that SARS-CoV-2 can infect dopaminergic neurons and disrupt dopamine production, this research provides valuable insights into the mechanisms underlying COVID-19-related neurological symptoms.
 
Moreover, the study underscores the need for ongoing research to explore the variant-specific effects of SARS-CoV-2 on the nervous system, as well as its potential implications for individuals with pre-existing neurological conditions like Parkinson's disease. As we continue to unravel the complexities of COVID-19, studies like this one bring us closer to developing targeted therapies and interventions to mitigate the neurological impact of the virus, improving the lives of those affected by this global pandemic.
 
The study findings were published in the peer reviewed journal: Experimental and Molecular Pathology.
https://www.sciencedirect.com/science/article/pii/S0014480023000254
 
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