SARS-CoV-2 infection may increase risk of brain degeneration seen in Parkinson’s disease

Brain fog, headache, insomnia are some of the neurological symptoms doctors have seen in COVID-19 patients. Neurological sequelae after viral infection are nothing new – in fact, following the 1918 influenza pandemic, it took nearly a decade for patients to develop the neurological syndrome called ‘post-brain parkinsonism’. But, the mechanisms by which viruses impact the brain are poorly understood. Now, Jefferson and his collaborators show in a new study performed on mice, that the SARS-CoV-2 virus responsible for the COVID-19 pandemic could increase the risk of brain degeneration seen in Parkinson’s disease.

Parkinson’s disease is a rare disease that affects 2% of the population over 55, so the increased risk is not necessarily a cause for panic. But understanding how the coronavirus affects the brain can help us prepare for the long-term consequences of this pandemic.”


Richard Smeyne, PhD, director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Vickie and Jack Farber Institute for Neuroscience and first author of the study

The research, published in Movement disorders May 17and, builds on previous evidence from the Smeyne lab showing that viruses can make brain cells or neurons more susceptible to damage or death. In this earlier study, researchers found that mice infected with the H1N1 strain of influenza responsible for the 2009 influenza pandemic were more susceptible to MPTP, a toxin known to induce some of the hallmarks of Parkinson’s disease: primarily loss of neurons expressing the chemical dopamine and increased inflammation in the basal ganglia, a region of the brain essential for movement. The results in mice were later confirmed in humans by researchers in Denmark, who showed that influenza nearly doubled the risk of developing Parkinson’s disease within 10 years of initial infection.

In the current study, the researchers used mice genetically modified to express the human ACE-2 receptor, which the SARS-CoV-2 virus uses to gain access to cells in our airways. These mice were infected with SARS-CoV-2 and allowed to recover. Importantly, the dose chosen in this study corresponds to moderate COVID-19 infection in humans, with approximately 80% of infected mice surviving. Thirty-eight days after the surviving animals recovered, one group was injected with a low dose of MPTP that would normally cause no loss of neurons. The control group received saline solution. Two weeks later, the animals were sacrificed and their brains examined.

The researchers found that COVID-19 infection alone had no effect on basal ganglia dopamine neurons. However, mice that received the low dose of MPTP after recovering from an infection showed the classic pattern of neuron loss seen in Parkinson’s disease. This increased susceptibility after COVID-19 infection was similar to what was seen in the influenza study; this suggests that the two viruses could induce an equivalent increase in the risk of developing Parkinson’s disease.

“We’re thinking of a ‘multi-hit’ hypothesis for Parkinson’s disease – the virus itself doesn’t kill neurons, but it makes them more susceptible to a ‘second hit’, like a toxin or a bacteria or even a underlying genetic mutation,” says Dr. Smeyne.

Influenza and SARS-CoV2 have been found to cause “cytokine storm” or an overproduction of pro-inflammatory chemicals. These chemicals can cross the blood-brain barrier and activate the brain’s immune cells – microglia. Indeed, the researchers found an increased number of activated microglia in the basal ganglia mice that recovered from SARS-CoV2 Although the mechanism is not fully understood, researchers believe that the increase in microglia inflames the basal ganglia and causes cellular stress, which lowers the threshold for neurons to withstand subsequent stress.

This study was co-led by collaborator Peter Schmidt, PhD, a neuroscientist from New York University. “We were concerned about the long-term consequences of viral infection,” Dr. Schmidt said. “Dr. Smeyne is a leader in this area of ​​research and Jefferson was the perfect site to perform the analysis.”

Researchers plan to determine whether vaccines can attenuate the experimental increase in Parkinson’s pathology linked to prior SARS-CoV-2 infection. They are also testing other variants of the virus, as well as doses corresponding to milder cases in humans.

Although their findings so far reinforce a possible link between the coronavirus and Parkinson’s disease, Dr Smeyne says there are some important caveats. “First of all, this is preclinical work. It’s too early to say if we’d see the same in humans, given that there seems to be a 5-10 year lag between any changes in the clinical manifestation of Parkinson’s disease in humans.” This lag, he says, however, could be used to our advantage. “If COVID-19 is found to increase the risk of Parkinson’s disease, it will be a major burden on our society and our healthcare system. But we can anticipate this challenge by advancing our knowledge of potential “second blows” and mitigation strategies.

Source:

Journal reference:

Smeyne, RJ, et al. (2022) COVID-19 infection increases susceptibility to oxidative stress-induced parkinsonism. Movement disorders. doi.org/10.1002/mds.29116.

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