The Flu and You: How Viruses Influence the Risk of Parkinson's
What causes Parkinson’s disease? This is a question that has been haunting the community since it was first described as a syndrome in James Parkinson’s “Essay on the Shaking Palsy” published in 1817. Prior to the late 1990s, clinicians and scientists labeled the cause as “idiopathic” or unknown. However, a group of physicians lead by Larry Golbe and Roger Duvoisin at the The University of Medicine and Dentistry of New Jersey (UMDNJ) identified a Greek family (now known as the Contursi kindred) who had many family members with Parkinson’s disease (PD). Later work by Robert Nussbaum, Mihael Polymeropoulos and their colleagues at the National Institutes of Health (NIH) identified a mutation in this family’s genome within the gene encoding alpha-synuclein. Fast-forward 20 years, and many more genes have been identified that cause PD. Despite all of this gene discovery, it appears that only 10-20% of the cases of PD has an identifiable genetic link. So, what is the cause of the other 80-90% of the cases? Most scientists think that it arises from exposure to an environmental agent coupled with sensitivity to its effects; thus, not everyone who is exposed will develop the disease. A number of these factors have been identified, including pesticides, heavy metals, and solvents. Our lab has been studying the effects of another agent in regard to its contribution to the development of PD, that being viruses.
The idea that viruses or other infectious agents may be a contributor to parkinsonism comes from a number of events. One of the most famous, is the parkinsonism that developed following the 1918 influenza pandemic. Here, people born during the time of this Spanish flu outbreak had a 2-3-fold-increased risk of PD than those born prior to 1888 or after 1924. Another link to viruses is the finding of “parkinsonian clusters”. These are groups of individuals who share common environments and develop parkinsonism at greater than normal rates. Several of these “parkinsonian clusters” have been described, including those living in Israeli kibbutz’s, group of college teachers, garment workers in a manufacturing factory and a group of actors, producers and technical staff working on a television series in Canada.
My labs interest in the role of influenza viruses in PD came from work being done by Dr. Robert Webster in the Department of Virology at St. Jude Children’s Research Hospital. In 2007, a postdoctoral fellow in his lab, Dr. David Boltz, was showing films he made of ducks who had been infected with the H5N1 Highly Pathogenic Avian Influenza virus. The ducks in his film had trouble initiating movement, had abnormal postures, and difficulty with balance and gait. Thus, for all intents and purposes, these animals looked like “birds with PD”. While this was an interesting observation, a postdoctoral fellow in my lab, Dr. Kennie Shepherd and another postdoc from the Webster lab, Dr. Kathy Sturm-Ramirez, continued this discussion; and through their persistence initiated a collaboration between my lab and the Webster lab.
When we looked at the brains of these infected ducks, we found a profound loss of neurons in their substantia nigra, similar to that seen in PD. This led us to a series of studies examining the direct effect of the H5N1 virus in mammals. In the secure BL3+ facility at St. Jude Children’s Research Hospital, David Boltz administered H5N1 into the noses of mice. A talented graduate student in my lab, Haeman Jang, then set about exploring what this virus did to the nervous system. Careful and painstaking studies showed that this virus was capable of entering the central nervous system by using a “back door” approach of traveling though the Vagus nerve, which connects the stomach and lung to the brain. Once in the brain, we showed that the virus could induce a large inflammatory response, increase the levels of alpha-synuclein (the main protein in Lewy bodies) and induce dopaminergic neuron loss in the substantia nigra. He also showed that the spread of the influenza virus throughout the brain was similar to the pattern of progression of developmental synucleinopathy in Parkinson’s disease described by Braak.
Our lab’s finding that H5N1 virus could induce parkinsonism in mice lead us to ask whether other more common strains of influenza could also contribute to developing PD. Around this time, the world encountered a novel influenza A subtype, CA/09 H1N1, that was responsible for the 2009 flu pandemic. Like the 1918 H1N1 Spanish flu, patients infected with the 2009 H1N1 were also, in some cases, developing encephalitis. Since St. Jude Children’s Research Hospital is a WHO Collaborating Center for Influenza, we were able to examine this flu strain for its neurotrophic and PD-inducing qualities. Since Dr. Webster was retiring from his storied career, he suggested collaborating with another talented influenza virologist, Dr. Stacey Schultz-Cherry, who had recently joined the faculty. Working with Dr. Shultz-Cherry, a postdoctoral fellow in my lab, Dr. Shankar Sadasivan, sought to determine if this strain of influenza, like H5N1, could induce parkinsonism. Unlike the H5N1 strain, the pandemic H1N1 did not enter the central nervous system (CNS). However we did find that the virus was able to still activate the immune system in the brain (cells called microglia). This surprising finding suggested that the adaptive immune system found in T- and B-cells that were activated by flu could transmit an inflammatory signal into the brain; likely through the actions of circulating inflammatory proteins the blood cells secreted called cytokines and chemokines. Additional studies showed that despite the increased inflammation, the H1N1 did not cause the loss of dopaminergic neuron in the substantia nigra, like we had seen with H5N1. Since the 1918 Spanish flu occurred many years before the outbreak of post encephalic PD, we performed experiments to test if the H1N1-induced inflammation made animals more susceptible to later exposures that in and of themselves would not normally lead a PD pathology. In a recent study just published, we report that prior infection with H1N1 makes dopaminergic neurons more susceptible to a chemical called MPTP, which is to model dopamine neuron loss in animals, and increase in susceptibility occurred long after the influenza infection was resolved. We then directly tested if the influenza was the direct cause of this increased susceptibility by either vaccinating mice against the flu or treating animals with Tamiflu® at the time of infection. In both cases, we showed that these mice were protected from the increased pathology induced by MPTP. All together, these studies support the idea that multiple exposures - over periods of time - can synergize to induce PD. Our identification of influenza as one of these factors and the finding that this “hit” can be eliminated by vaccination, or prompt treatment with anti-viral medications after infection, provides another reason to get a flu vaccine.
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Richard Smeyne, PhD, was a Hot Topics presenter at the WPC 2016. He is currently a Professor in the Department of Neuroscience at the Vickie and Jack Farber Institute for Neuroscience and Director of the Jefferson Comprehensive Parkinson's Disease and Movement Disorder Center in Philadelphia PA.
Twitter: @RSmeyne
Watch Dr. Smeyne’s WPC 2016 Hot Topics talk.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.