One of the first things that happens in neurodegenerative diseases is that neurons stop communicating with each other. And when neurons stop talking, they die.

One hypothesis for this phenomenon is that the neurons get overly excited — so excited that, in simple terms, they burn themselves out. Researchers have known about the possible link between this neural “excitotoxicity” and neurodegeneration for decades. But work is still needed to understand the mechanisms responsible for these changes.

Dr. Janice Robertson, a molecular cell biologist and the James Hunter Family Chair in ALS Research at the University of Toronto, is trying to change that. With the support of an ALS Canada-Brain Canada Discovery Grant, she and her team are attempting to answer exactly how certain proteins (or their absence) contribute to cell burnout.

Though she’s focused on a specific gene mutation, her findings could help us gain a better understanding of basic biological mechanisms in all types of ALS. This work also has exciting implications for current gene therapy clinical trials.

A communication breakdown

At least 50 per cent of people living with ALS will develop some level of cognitive impairment over the course of their illness. The most common genetic cause of these specific ALS cases is a mutation in a gene called C9ORF72 – and when patients have this mutation, there is a loss of normal C9ORF72 proteins (C9 for short).

Researchers still don’t know exactly what C9 proteins do. But thanks to previous research by Dr. Robertson, we do know where they live: on the synapse of a neuron, which is where cell-to-cell communication happens – and where excitotoxicity can do the most damage.

Dr. Robertson and her team are using the Discovery Grant to ask a number of questions that will help deepen our understanding of the role of C9 proteins in excitotoxicity, including whether mice who have had the C9 gene removed are more prone to seizures.

With this grant, Dr. Robertson hopes to confirm a previous finding that cells without C9 proteins see an increase in a neurotransmitter receptor, called GluA1, which is an important glutamate receptor found on the synapses of neural cells. If you have too much GluA1, your cells can get – you guessed it – overexcited.

A cell biologist and an electrophysiologist walk into a lab…

Dr. Robertson has been a leading ALS researcher for years, but this is the first time she’s collaborated with an electrophysiologist, Dr. Liang Zhang, also at the University of Toronto.

“It’s particularly novel for Dr. Robertson to collaborate with an electrophysiologist to do this important work,” said Dr. David Taylor, Vice President of Research for the ALS Society of Canada. “We’re excited by the possibilities of such a powerhouse collaboration.”

“I work on the cell level, but Dr. Zhang is looking more at the macro level. He’s asking questions about how neurons function together as a whole system,” Dr. Robertson said. “This type of multidisciplinary collaboration is absolutely crucial for our type of research. You can’t just work in your own sandbox.”

Possibility beyond the bench

“We believe studying C9ORF72 and its role in causing this excitotoxicity through elevation of this glutamate receptor will have an impact on all of ALS, because it will help us understand an important underlying biological mechanism,” Dr. Robertson said.

“Dr. Robertson does amazing work,” said Dr. Taylor. “This study will add another dimension to our search for the most effective way to treat the disease.”

According to Dr. Catherine Ferland, Chief Research and Programs Officer at Brain Canada, partnerships such as the one between Brain Canada and the ALS Society of Canada have advantages far beyond the much-needed financial investments in ALS research. “We open the door to a more hopeful future every time we advance our understanding of a rare and debilitating disease like ALS.”

Funding that makes an impact

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $24 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease. In 2022, nine projects awarded through the 2021 Discovery Grant Program will benefit from $1.125 million in funding.

The Discovery Grant Program has been made possible with the financial support of Health Canada, through the Canada Brain Research Fund, an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada, and of the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.

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Posted in: Research