Characterizing enterovirus disruption of autophagy as a disease mechanism for ALS

A group of viruses called enteroviruses can cause a variety of infectious illnesses that are usually mild with symptoms that may include fever, respiratory distress, flu-like muscle aches and rashes. However, some enteroviruses are more serious, like enterovirus D68 that can cause severe respiratory illnesses 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.

Yasir Mohamud and colleagues at the University of British Columbia recently discovered that infecting motor neurons with enteroviruses can cause changes that are remarkably similar to those seen in ALS. The similarities include TDP-43 protein abnormalities and a reduced ability for motor neurons to clear and recycle cellular waste in a process called autophagy. Based on these observations, Mohamud believes that enterovirus infection may play an important role in how ALS begins and progresses.

In this project, Mohamud will use mouse models to investigate whether enterovirus infection causes TDP-43 toxicity and disrupts the autophagy process. He will also see if he can restore autophagy using compounds designed to inhibit the virus and examine whether enteroviral infection encourages the spread of misfolded TDP-43 and SOD1 from cell to cell, possibly explaining progression of ALS throughout the body.

As the majority of ALS cases are sporadic, meaning that they occur without any apparent family history of disease, Mohamud hopes that this project will provide a deeper understanding of the underlying triggers of sporadic ALS and reveal a promising new target for treatment development.