A group of viruses called enteroviruses usually cause mild illnesses with symptoms that may include fever, respiratory issues and flu-like muscle aches, similar to the common cold. However, some can cause more serious health problems, such as enterovirus D68 that can cause severe respiratory illness or the poliovirus that causes polio.
Some researchers have long suspected that enteroviruses may be linked to ALS due to their ability to harm motor neuron function, but the available evidence of a causal link has so far been inconclusive. “Some people with ALS have shown evidence of prior exposure to enterovirus infection while others did not,” said Yasir Mohamud, a PhD candidate who has been working in the lab of Dr. Honglin Luo at the University of British Columbia since 2016.
Mohamud recently received a trainee award of $75,000 funded by the ALS Canada Research Program, in partnership with Brain Canada, to explore a potential relationship between enterovirus infection and ALS. “This project will be the first to see if enterovirus can cause ALS pathology in mice. If so, that will suggest that using antivirals to target enteroviruses might be an exciting new therapeutic strategy in the future,” said Mohamud. “If we do not find a causal link, creating these models of ALS with enterovirus will still be very useful for studying ALS in future research.”
A novel discovery
Dr. Luo and her team have been studying enteroviruses for 15 years, focusing mainly on cardiovascular diseases. Recently, they discovered that infecting motor neurons with enteroviruses produces changes with striking similarities to those seen in ALS. The similarities included TDP-43 protein abnormalities and a reduced ability for motor neurons to clear out cellular waste in a process called autophagy. “Based on our findings, we believe that enterovirus could be a causal factor or a risk factor for triggering ALS,” said Mohamud.
Advancing ALS research
The Luo laboratory will test whether normal mice develop the signs and symptoms of ALS after they are infected with an enterovirus and whether virus accelerates the progression of ALS in mice that have been genetically modified to model the disease.
They expect to find that the mouse models of ALS will show more of the typical TDP-43 protein irregularities seen in ALS — redistribution of the TDP-43 protein from the nucleus to the cytoplasm and its clumping in motor neurons and a disrupted ability to clear out cellular waste products, such as abnormal TDP-43 protein and other cellular waste products. This buildup is believed to cause toxicity.
Mohamud will explore how enterovirus spreads in the central nervous system of the mice and whether it promotes the spread of abnormal TDP-43 and SOD1, another protein that can become misfolded and lead to motor neuron toxicity in ALS. For this part of the project, he will collaborate with Dr. Neil Cashman, director of the Vancouver Coastal Health ALS Clinic and an ALS researcher at the University of British Columbia. Dr. Cashman’s research focuses on protein-misfolding processes in neurodegenerative diseases. He discovered that SOD1 protein abnormalities can trigger TDP-43 protein problems in ALS and may play a role in how the toxicity spreads throughout the nervous system.
This research project is one of 6 trainee awards funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. ALS Canada trainee awards support Canada’s emerging ALS researchers, whether they are doctoral students, postdoctoral researchers, or clinical research fellows. Trainee awards encourage young researchers to choose ALS as their area of focus, helping to ensure that Canada has a strong base of talented ALS researchers today and into the future.
The funding of the project followed a rigorous scientific assessment by panels of ALS experts. The panellists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.
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