According to a new study, SARS-CoV-2, the virus that causes COVID-19, can infect dopamine neurons in the brain and trigger senescence - when a cell loses the ability to grow and divide.
The researchers, from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center and Columbia University Vagelos College of Physicians and Surgeons, suggest that further research may shed light on the neurological symptoms associated with long COVID, such as brain fog, lethargy and depression.
The findings, published Jan. 17 in Cell Stem Cell, show that dopamine neurons infected with SARS-CoV-2 stop working and send out chemical signals that cause inflammation. Normally, these neurons produce dopamine, a neurotransmitter that plays a role in feelings of pleasure, motivation, memory, sleep and movement. Damage to these neurons is also connected to Parkinson's disease.
"This project started out to investigate how various types of cells in different organs respond to SARS-CoV-2 infection. We tested lung cells, heart cells, pancreatic beta cells, but the senescence pathway is only activated in dopamine neurons," said senior author Shuibing Chen, director of the Center for Genomic Health, the Kilts Family Professor of Surgery and a member of the Hartman Institute for Therapeutic Organ Regeneration at Weill Cornell Medicine. "This was a completely unexpected result."
Previously, Chen led the effort to generate multiple cell types from human stem cells and tested them to see which ones SARS-CoV-2 could infect. This allowed the researchers to survey the spectrum of tissues that might be infected during COVID, which has a diverse array of symptoms in different patients. They also studied autopsy samples from patients infected with the virus to confirm their observations from the lab grown cells.
Surprisingly, they found that around 5% of dopamine neurons exposed to SARS-CoV-2 were infected. "The infection rate of dopamine neurons isn't as high as lung cells, the virus's main target," Chen said, "but even a small population of infected cells can potentially have a severe effect."
Interestingly, not all brain cell types were vulnerable to viral infection. The researchers observed that cortical neurons were not permissive to SARS-CoV-2 infection under identical experimental conditions.
The researchers used transcriptional profiling to identify how SARS-CoV-2 infection modified gene activity and the resulting changes in the way cells behaved.
"We discovered that only dopamine cells had the senescence pathway activated," Chen said. In stark contrast, the genes in the senescence pathway were not significantly turned on when SARS-CoV-2 infected lung organoids, pancreatic cells, liver organoids or heart cells.
The researchers found that the gene signatures - the unique pattern of gene activity - from the infected lab-grown dopamine neurons and the dopamine neurons from COVID autopsy samples were the same. This included genes that triggered chemical signals for inflammation.
Next, they looked for ways to protect the neurons to reduce the risk of neurological defects when a patient is infected by the virus.
The researchers tested drugs already marketed for various conditions to find one that either prevented SARS-CoV-2 infection or rescued infected dopamine neurons from senescence. The screen identified three drugs that blocked SARS-CoV-2 infection thereby preventing the dopamine cells from senescence: riluzole (treats ALS, or Lou Gehrig's disease), metformin (treats diabetes) and imatinib (treats cancer). Further study on these drugs may lead to a way to prevent the virus's attack on the brain.
Though most people are exposed to COVID, only certain individuals will be impacted since many factors are involved in the risk for neurological symptoms such as severity of the disease and genetics. Human population studies are exploring this aspect further.
While the clinical relevance of these findings is still unclear, since dopamine neuron senescence is a hallmark of Parkinson's disease, the researchers suggest that long COVID patients should be monitored for an increased risk of developing Parkinson's-related symptoms. To date, Parkinson's symptoms have not been widely reported in population studies.
Co-authors included Dr. Lorenz Studer, director of the Center for Stem Cell Biology at Memorial Sloan Kettering Cancer Center; Dr. David D. Ho, Clyde '56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons; and Dr. Robert Schwartz, associate professor of medicine in the Division of Gastroenterology and Hepatology, a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center.
This research was funded by grants from the National Institutes of Health; the Department of Surgery at Weill Cornell Medicine; the Michael J. Fox Foundation for Parkinson's Research; and New York State Stem Cell Science, a program of the state Department of Health.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Drs. Shuibing Chen and Robert Schwartz.
Karen Hopkin is a freelance writer for Weill Cornell Medicine.
