Learning more about how gene mutations can cause ALS


Updated October 20, 2017

In the late 1980s, Dr. Neil Cashman was completing a neurology fellowship in ALS at the University of Chicago. At that time, little was known about the genetics or biology of ALS and Dr. Cashman became captivated by trying to understand the cause of the progressive paralysis he observed in his patients.

The Prion Hypothesis

Proteins, the substances responsible for almost all cellular functions, are molecules that consist of long chains of smaller units called amino acids. In order to complete its intended function within a cell, a protein must first fold into the appropriate 3D shape. If a protein misfolds, meaning it does not fold into the correct shape, the outcome can be toxic. A protein is said to have prion-like behaviour when it fulfills two major criteria: first, it must be able to cause other normally-folded proteins to change their shape and adopt a toxic shape. Second, it must trigger a chain reaction, moving from cell to cell creating a domino effect of toxic protein misfolding that spreads throughout the nervous system. Well-known prion diseases include scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans.

Targeting ALS

When Dr. Cashman read about the prion hypothesis, first published by Dr. Stan Prusiner in 1982, “it totally rang a bell that ALS could be a propagated protein misfolding disease,” he says. Now a professor in the Department of Neurology at the University of British Columbia and the Director of the Vancouver Coastal Health ALS Clinic, Dr. Cashman has been working on this theory ever since.

Early on, Dr. Cashman hypothesized that the misfolding of a protein called superoxide dismutase 1 (SOD1) may contribute to the breakdown of cells in the nervous system in ALS. Mutations in the SOD1 gene represent the second most common cause of the inherited (familial) form of ALS. Researchers still do not know the exact mechanisms by which mutations in SOD1 lead to the death of neuronal cells; however, studies suggest that misfolding may cause SOD1 to gain a toxic function.

Since mutations in SOD1 only account for approximately 2% of all ALS cases, Dr. Cashman wanted to find out if normal, non-mutated (wild-type) SOD1 could also adopt this abnormal and toxic shape. His theory was that if normal SOD1 could misfold, then SOD1 may also play a role in sporadic (non-familial) ALS, which represents more than 90% of all cases.

A breakthrough came when Dr. Cashman was able to show just that. “We found that mutant SOD1 is able to convert normal wild-type SOD1 to a disease-associated from that can transmit from cell to cell,” he describes.

Pushing the boundaries even further, Dr. Cashman later showed that when two additional prominent ALS proteins, TDP-43 and FUS, are mutated they are able to cause normal SOD1 to misfold in cells. Dr. Cashman explains that “this is very exciting in the context of sporadic ALS because TDP-43 abnormalities are present in approximately 98% of all ALS cases.”

Overall, Dr. Cashman’s work suggests that SOD1 may play a wider, more general role in ALS than previously thought to be the case. If prion-like induced misfolding of normal SOD1 does contribute to the breakdown of cells in the nervous system in ALS, then treatment strategies designed to block the domino-like misfolding should be successful at treating both the sporadic and familial forms of ALS. Dr. Cashman explains that “while we don’t have a definitive answer as of yet, we are continuing to work on this hypothesis.”

Progress in ALS research

Having been successful in attaining a number of grants through ALS Canada Research Program competitions, Dr. Cashman notes that “ALS Canada has stepped up to the plate in funding basic and translational ALS research in Canada, because of the donations of generous people” and speaks positively about the difference the country’s ALS research community is making on an international scale: “Canadians have always punched above their weight in ALS research, both in terms of publications and impact,” he says. “For reasons I’m not 100 per cent sure of, we seem to be a country in which great breakthroughs are being made and will continue to be made.”

Reflecting on his time 30 years ago at the ALS clinic at the University of Chicago, Dr. Cashman still remembers three young women who suffered from rapidly progressive ALS. With no information on the genes linked to ALS or the biology behind the mutations, Dr. Cashman remembers feeling “overwhelmed by the tragedy and deciding to make a vow to make some kind of contribution to ALS research.” Today, Dr. Cashman’s outlook on the state of the field has changed significantly. When asked his opinion on where ALS research is currently at, Dr. Cashman affirms that “there has never been a time in history where more people are working on ALS. I am not only hopeful, but truly optimistic, that soon there will be an effective treatment for ALS.”

ALS Canada Virtual Research Forum

Update: Dr. Cashman was one of more than 20 speakers who participated in the ALS Canada Virtual Research Forum in August. You can listen to his full presentation online here.

Posted in: Research