Structural biology research takes aim at rare neurodegenerative disease

Rachel Harding leads research to understand protein responsible for Huntington’s disease and advance drug discovery

Families affected by Huntington’s disease know firsthand the devastation this rare neurodegenerative disease can cause. Medications can help manage the symptoms, but no treatments are available yet that can target the root cause of the disease. So for many families, research is an important source of hope.

Rachel Harding, assistant professor at U of T’s Leslie Dan Faculty of Pharmacy, is committed to sharing her research and communicating with the patient community and those affected by the disease.

“I'm really passionate about it. What's the point of doing science if it's not connected to the people who are most impacted by what you're studying?” says Harding, who is also principal investigator at Structural Genomics Consortium at the University of Toronto. “Connecting to these families and hearing their perspectives is valuable. Sharing research also gives them agency so that they know what's going on and they can make informed choices about clinical trials and potential new therapies.”

Harding is a structural biologist and biochemist who examines how the structure of proteins affects their functions. After completing her undergraduate and graduate degrees at the University of Oxford in the United Kingdom, she moved to Toronto to do a postdoctoral fellowship examining proteins related to cancer.

But early in her fellowship, she started a project to study the structure of the protein responsible for Huntington’s disease, called huntingtin, and she was fascinated by the science behind it.

Huntingtin is a large protein, but when a genetic mutation makes one small change to the protein’s structure, it leads to a catastrophic series of events that causes nerve cells in some parts of the brain to die. This results in symptoms such as involuntary movements and changes in cognition and behaviour.

“I was very interested in understanding how the function of the protein changes because of a relatively small change in the structure,” she says. “It's a really interesting paradigm for structural biology, and it's something that we still have so many unanswered questions about.”

Harding is now leading a research program that examines the structure of the huntingtin protein, in both its healthy and disease-causing forms, and its role in cells. By understanding how changes in the structure influence the protein’s function, researchers can learn how the protein causes disease and look for parts of the protein that could be targeted with new drugs.

She recently received a five-year, nearly $1-million grant from the Canadian Institutes of Health Research to develop chemical tools that will allow researchers to study the huntingtin protein in detail. Her group previously collaborated with a team in Tokyo to find molecules that bind to the huntingtin protein, and they are now studying these molecules to see how and where they attach to the protein. They will then use these molecules to better understand what the huntingtin protein does  inside cells and how it causes disease.

In her related research at the Structural Genomics Consortium, she is leading work to identify molecules that can bind and alter a large number of proteins, which will help jumpstart drug discovery for many different diseases.

Ultimately, with a better understanding of the disease-causing protein and molecules that can bind to it, Harding’s program is meant to lead to new therapies by identifying potential targets for new drugs.

“When you make a chemical tool for a protein, it allows you to uncover its biology and really dive into some of its function,” says Harding. “But the happy byproduct of chemical tools is that they also serve as really great foundations for drug discovery programs, and we're also very interested in that.”

Huntington disease community is highly motivated and engaged

Tamara Maiuri was pursuing a career in cancer research, earning a PhD in medical biophysics from the University of Toronto, until her family found out that her mother carried the gene for Huntington’s disease. She then pivoted her research to focus on Huntington’s disease and is currently a research associate with a team at McMaster University where she studies the huntingtin protein and how it is disrupted in disease. She has volunteered with the Huntington Society of Canada since she was a child, and is also a member of their research council, along with Harding.

As both a researcher and family member, Maiuri knows well how important research is to the community.

“Research is hope! Research is a way for people to envision a path that doesn’t lead to the fate experienced by their affected loved ones,” she says. “It allows people to envision a future in which they, or their kids, won’t suffer that same fate.”

Maiuri and Harding both say that families affected by Huntington disease are highly motivated, engaged and knowledgeable about research, and they are often stay up to date on new developments such as clinical trials.

“I think the biggest driver of HD community engagement is the generational nature of the disease. It’s not just the gene that’s inherited, it’s the community,” says Maiuri. “Many people feel better when they’re taking action and informing themselves, and multi-generational connections tighten the community as they work together for the cause.

The keen interest of families is one reason that Harding is committed to sharing her research with other Huntington’s researchers and the public, and connecting with patients and families.

Harding is co-editor-in-chief of HDBuzz, a trusted online source of news for the Huntington’s disease community, where Maiuri is also a writer. They both write and edit plain language articles and shares live updates from research conferences. Harding also encourages trainees in her lab to do the same.

She says that communicating research to those most affected by the disease is important for giving families hope and helping her stay motivated and inspired to continue her work.

“Our overall message on HDBuzz is meant to keep people engaged, educated, informed and hopeful. There have been a lot of ups and downs in Huntington’s research, but we have to keep moving forward,” says Harding. “As researchers, we know the urgency within the community and working with these families gives us a lot of motivation.”