How does the loss of the normal function of DNAJC7 cause ALS?

Understanding how mutation in “first responder” gene can lead to neurodegeneration in ALS

“It’s been such an honor to be a part of this community. We are scientists, but we’re also humans, and we know how devastating this disease is. As researchers, we wake up every day wanting to do good science because we want to help the patients we work with.” – Dr. Sali Farhan

Thanks to new funding from the ALS Society of Canada and Brain Canada, Dr. Martin Duennwald of Western University, an expert on protein misfolding in neurodegenerative disease, is coming together with Dr. Sali Farhan, an up-and-coming Canadian researcher at The Neuro (Montreal Neurological Institute-Hospital). Together they will explore how mutations in DNAJC7 impede its ability to act as a “first responder” within cells, and how this failure may contribute to ALS.

In 2019, while still a postdoctoral fellow, Dr. Farhan led a collaborative effort that identified DNAJC7 as a causal factor in ALS; working from a large data set, Farhan had demonstrated that mutations in DNAJC7 disabled its protective function.

Now, together with Dr. Duennwald, she is building on this discovery in a joint project.

AMBITIOUS INQUIRY BY AN EARLY-CAREER RESEARCHER

While completing a fellowship at Massachusetts General Hospital and the Broad Institute of MIT and Harvard, Farhan led a sizeable study comparing nearly 4,000 ALS cases with close to 8,000 control samples. “It was the largest exome-based case-control study in ALS,” she says, referring to the study’s focus on the aspects of DNA that contain protein coding information. “We were asking, ‘Is there a unique signal in ALS cases that’s absent in controls?” Her analysis revealed known genetic players in ALS – but also turned up something previously unknown.

“We started to observe some novel signals in a subset of cases, including for a gene called DNAJC7,” says Farhan. “It encodes a protein that, when mutated, gives rise to ALS.” More evidence followed: her team confirmed this finding in ALS patient cells, noting that those with genetic mutations produced little to no DNAJC7 protein.

A NEW PROJECT: HEAT SHOCK, FOLDING AND MISFOLDING

The next step was to connect with an expert who could help unlock the secrets of DNAJC7’s unique role as a heat shock protein – when functional, these proteins stand guard against trouble at the cellular level.

This is where Dr. Martin Duennwald came in. “Sali is a gene hunter: she identifies the genes that are important for ALS, along with mutations that can cause the disease,” Duennwald says. “And then my team can find out how it happens at the mechanistic level. Together, that’s a very strong combination.”

What could ALS have in common with a paper airplane that won’t fly straight? In both cases, poor folding can be a fatal flaw. “Every protein in our body has to form into a very distinct three-dimensional structure,” Duennwald explains. “When it folds properly, the protein can attain the proper structure. But when it goes awry, we say it misfolds; this is a major hallmark of neurodegenerative diseases, including ALS.”

In healthy people, certain safeguards prevent and fix protein misfolding. These include heat shock proteins like DNAJC7, first responders that get activated by cellular stress, and can then step in and correct emerging problems to ensure that proteins fold properly.

Unlocking this complex origami is a big part of Duennwald’s work. “These mechanistic underpinnings are what really keep me up at night,” he says, “along with what we do in the lab to figure out how it goes together in ALS.” In his work with Farhan, this means investigating why DNAJC7 can fail as a responder.

EXPLORING THE MUTATION – AND ITS ABSENCE

For their joint project, Duennwald’s lab will study how misfolding resulting from the loss of DNAJC7 function leads to ALS specifically.

One portion will involve Duennwald implementing the mutation in yeast models to understand how it operates at the cellular level. Farhan will also extend her work to include additional patient samples from around the world, gaining a fuller picture of how DNAJC7 mutations figure in the global ALS population. They will also gather clinical information from people with DNAJC7 mutations, and partners at Harvard University will analyze motor neurons and other cell types derived from these individuals to better understand the clinical characteristics of this form of the disease. Together, they will also look into the transcriptional signature of the gene: “We want to understand how this ‘bad cop’ influences the other parts of the genome,” says Farhan. “Is it just acting alone in this specific pathway, or is it affecting multiple different pathways?”

It is early days yet, but Farhan explains that in the longer term, the team aims to uncover not only how the DNAJC7 mutation operates, but also how functional DNAJC7 acts in ALS patients who do not carry the mutation. “We know this specific gene is involved, and it’s possible that a future therapy targeting the DNAJC7 pathway – for instance, augmenting its function – could be beneficial to a patient regardless of whether they carry the mutation.”

A RESEARCH COMMUNITY WITH A SHARED PURPOSE

At this exciting moment, Farhan feels a deep sense of gratitude: “It’s been such an honor to be a part of this community,” she explains. “We are scientists, but we’re also humans, and we know how devastating this disease is. As researchers, we wake up every day wanting to do good science because we want to help the patients we work with.”

This intention is part and parcel of the funding program: “The Discovery Grant Program creates opportunities for unique multidisciplinary teams to ask innovative questions,” says Dr. Viviane Poupon, President and CEO of Brain Canada. “We envision a future without ALS, and we believe that collaboration is the best way to get there.”

Dr. David Taylor, Vice President of Research for the ALS Society of Canada, agrees: “Discovery Grants support unique collaborations – in this case, a geneticist and a protein biologist combining their expertise to gain a biological understanding of a new discovery,” he says. “And it’s exciting to support early career researchers to advance the novel ideas they bring to the field.”

For his part, Duennwald feels this spirit of collaboration is a singular characteristic of the Canadian ALS research community: “It’s unique in this regard: everyone shares their knowledge and expertise, and there’s no petty competition, because we all have the same goal,” he says.

“We all want to make ALS a manageable, curable disease as soon as possible.”

Funding that makes a difference

The Discovery Grant Program makes these connections possible with a funding model that favours interdisciplinary collaboration, bringing the best minds together to tackle complex problems. Discovery Grants give promising novel ideas the fuel they need to gain traction; in 2021, up to eight projects will benefit from $1M in total funding.

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $23 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.

The Discovery Grant Program has been made possible by Brain Canada, through the Canada Brain Research Fund (with financial support from Health Canada) and 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.