How “accidental” discoveries can lead to new insights in ALS biology

“We need to understand the fundamentals, we need to understand the underlying cell biology so that we can create good, rationally designed therapies.” – Dr. Christine Vande Velde

“Everything started with a discovery we found by accident,” said Dr. Christine Vande Velde, a cellular biologist at the CHUM Research Centre at the University of Montreal.

More than 10 years ago, Dr. Vande Velde’s lab stumbled onto something interesting: a unique protein isoform called hnRNP A1B (or A1B for short) that was found primarily in motor neurons in the central nervous system.As an ALS researcher, that piqued her interest, as motor neuron degeneration is the hallmark of the disease. Understanding the unique biology of these cells is critical to one day developing effective therapies.

Fueled by an ALS Canada-Brain Canada Discovery Grant, Dr. Vande Velde and her collaborators are bringing years of serendipitous discoveries together to better understand the function – or dysfunction – of A1B in motor neuron function so researchers can figure out this debilitating disease.

Building on a Decade of Discovery

That foundational discovery happened in 2011, “And it’s been kicking around since then,” said Dr. Vande Velde. “I had a gut feeling it was important.” After a decade of hard work investigating the protein, the pieces are coming together.

Researchers have known for a while that changes to TDP-43, an RNA binding protein that usually lives in the nucleus of a cell, is a critical piece of the ALS biology puzzle.

Previous work from the Vande Velde lab revealed that TDP-43 has a role in regulating the splicing of a gene called HNRNPA1. Depending on how the HNRNPA1 code is read within a cell, two different forms of the protein can be created: hnRNP A1 and hnRNP A1B (an elongated form). Both forms of the protein likely play a role in moving RNA (our cell’s “messengers”) across a whole motor neuron – a huge job, as motor neurons extend from the central nervous system to the outer reaches of our fingers and toes.

“We did some digging, and there’s very little research on A1B,” Dr. Vande Velde said. It was time to get to work.

A1B: The Goldilocks isoform

Since then, Dr. Vande Velde has learned that when TDP-43 is reduced, we start to see more of the alternative A1B form of the protein in motor neurons. This led to the question: what happens when the ratio of A1B and its normal form is off?

On the other side of her lab, scientists are looking at questions related to cell stress. They soon realized that when motor neurons are stressed, the ratio of the normal protein and the alternative A1B form changed.

“We think A1B is like Goldilocks. You can’t have too much and you can’t have too little,” Dr. Vande Velde explained.

All these related insights form the basis of the questions Dr. Vande Velde is asking with the help of the Discovery Grant: what is the main function of A1B? And what happens to cells when there is too much A1B? And where does cell stress fit into all of this? Finding answers to some of these questions is crucial to understanding the larger biological picture of ALS.

“It’s incredibly complex biology, so every little gain in understanding we get helps us get a more fulsome picture, allowing us to eventually identify a therapeutic target for ALS,” said Dr. David Taylor, Vice President of Research for the ALS Society of Canada. “If we understand why something is becoming toxic, maybe we can intervene therapeutically and slow down the progression of motor neuron degeneration.”

“Luck favours the prepared mind”

“In my lab, we read widely,” said Dr. Vande Velde. She described how she and her colleagues regularly investigate how insights from cellular mechanisms involved in other diseases could be applied to their ALS research. This open-mindedness fuels new insights into their own ALS-specific research questions.

Her favourite saying is one she learned as a graduate student: “Luck favours the prepared mind.” And it shows. Many of the questions she and her collaborators are asking with this Discovery Grant are fueled by “serendipitous” connections she and her team have made over the years that have paired their fertile reading with their own research.

This openness to new ideas is coupled with a strong commitment to collaboration. For this project, Dr. Vande Velde is working with Dr. Marlene Oeffinger, a biochemist at the Montreal Clinical Research Institute, an affiliate of the University of Montreal.

“Dr. Oeffinger helps us methodology-wise, figuring out how to get at some of the questions we’re asking,” said Dr. Vande Velde. “She is an outstanding researcher that will help us get at what this unique protein might interact with in the neuron. That’s why I love collaborating. I simply don’t know how to do everything.”

Punching above their weight

Dr. Vande Velde said her research is motivated by more than a love for science.

She is particularly inspired by the community of ALS patients and families she’s met over the years. “I want to express my thanks to the families who have invested their time raising funds and awareness for ALS research. The ALS community is punching above its weight,” she said.

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.

“After eight years working together, we’ve been able to invest so much in ALS research,” said Dr. Catherine Ferland, Chief Research and Program Officer at Brain Canada. “This partnership benefits both researchers and those living with ALS, and we are already seeing the rewards of this investment.”

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 Foundation, 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.

Read more

• Brain Canada: Funding Brilliance Daily
• ALS Society of Canada: research and patient advocacy for a future without ALS
• All 2021 Discovery Grant recipients

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