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Aaron Gitler, PhD, Received the Sheila Essey Award for Research in ALS. This Is Why.

Article In Brief

This year's recipient of the Sheila Essey Award discusses his research on the association of TDP-43 and ataxin-2 with an increased risk for amyotrophic lateral sclerosis.

There are two types of research a scientist can pursue, said Aaron Gitler, PhD, the Stanford Medicine Basic Science Professor at Stanford University.

“You can do something that is safer and the result is predictable, but I think that's less impactful and interesting than doing something where you don't know what the result will be,” Dr. Gitler said. “I don't want to make it seem like we're always swinging for the fences. We have safer experiments as well. But we didn't know how the TDP-43 [TAR DNA-binding protein 43] studies would turn out. I would wake up thinking about it and go to sleep thinking about it.”

As it happened, Dr. Gitler's research into TDP-43 worked out so well that he was awarded the 2019 Sheila Essey Award for research into the causes, prevention, and cure for amyotrophic lateral sclerosis (ALS). Jointly honored by the AAN, the ALS Association, and the American Brain Foundation, Dr. Gitler was recognized in May at the AAN Annual Meeting; the $50,000 prize will support his continuing ALS research.

“I am very grateful to receive this award,” Dr. Gitler said. “In looking at the list of previous Sheila Essey Award recipients, they are all my scientific heroes and role models. It is very humbling to have the opportunity to make a small contribution to ALS research.”

Investigating TDP-43

With prior research showing that the misfolded clumps of the TDP-43 protein is associated with most cases of ALS, Dr. Gitler set out to see what would happen if, one by one, he blocked each gene in the genome. While blocking the gene for TDP-43 itself would be unwise, as it is required for many other functions, he reasoned that perhaps removing another gene would ameliorate the disease-causing clumping.

“I don't want to make it seem like we're always swinging for the fences. We have safer experiments as well. But we didn't know how the TDP-43 [TAR DNA-binding protein 43] studies would turn out. I would wake up thinking about it and go to sleep thinking about it.”

—DR. AARON GITLER

To start off, Dr. Gitler and his team worked with a simple model system—the baker's yeast cell. He found that the human ALS protein TDP-43 could also form clumps in yeast cells as it does in neurons. But since the yeast genome was much smaller than the human genome he could screen through all of the genes much more rapidly.

“We looked for genes that could make the clumping worse or better,” Dr. Gitler explained. “We had in our freezer a collection of different yeast strains, in each of which a single gene is deleted—one for each of the 6,000 yeast genes. We found that some yeast gene deletions made the cells worse, but one in particular made them better, and almost resistant to TDP-43 clumping. It's called PBP1 in yeast. The human homologue is called ataxin-2. I thought, okay, this might be an interesting gene to work on.”

Other scientists' research had previously shown that excessive repeats of three nucleotides, CAG, caused either Huntington's disease or spinocerebellar ataxia 2 (SCA2), depending on which gene had the excess number of repeats.

“Twenty-two is the healthy normal level of repeats in the gene that codes for ataxin-2,” Dr. Gitler said. “Thirty-five is the threshold to cause SCA2. I was wondering if a repeat of more than 22 but less than 35 could cause ALS. A kind of intermediate level. That was my hypothesis.”

He measured the number of repeats in the genomes of approximately 1,000 ALS patients and 1,000 healthy individuals and discovered that approximately 5 percent of the ALS cases had between 27 and 32 of the intermediate repeats.

“Five percent might not sound like a lot to you and me,” Dr. Gitler said, “but it's actually one of the most common genetic contributors to ALS. I say ‘contributors’ rather than ‘causes.’ Some people may have the repeats and never get ALS. But we think that having these repeats increases a person's risk of developing ALS.”

More research from his lab showed that the excessive number of repeats in ataxin-2 probably made the protein more stable, so there was too much of it around in the cell, which could cause problems—maybe by coaxing TDP-43 to form more clumps.

So Dr. Gitler next decided to look for a way to lower the amount of ataxin-2. He took mice engineered to express high levels of the TDP-43 protein and crossed them with a line of mice that lacked the ataxin-2 gene. Those with two normal copies of the ataxin-2 gene lived for about 30 days, while mice with only one functioning copy lived a bit longer. But those in whom both copies of the ataxin-2 gene had been removed lived over 300 days.

Finally, in hopes of finding a therapeutically applicable treatment in humans, Dr. Gitler's lab collaborated with Ionis Pharmaceuticals, Inc., to develop an antisense oligonucleotide that blocks the ataxin-2 gene. As described in his 2017 paper in Nature, a single administration of the antisense oligonucleotide to the central nervous system of the TDP-43 mice markedly extended their survival.

“Because TDP-43 aggregation is a component of nearly all cases of ALS,” the paper concluded, “targeting ataxin-2 could represent a broadly effective therapeutic strategy.”

Toxicology trials in larger animals are now being planned by Ionis in partnership with Biogen, Dr. Gitler said. Although he does not expect to be involved if they reach the stage of clinical trials, “I will be rooting for it on the sidelines,” he said.

After obtaining his undergraduate degree at Penn State, and a PhD at the University of Pennsylvania, Dr. Gitler pursued his postdoctoral fellowship at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology. There he began studying the basic mechanisms of protein folding and misfolding under his mentor, the late Dr. Susan Lindquist, who passed away in 2016.

“She was a really amazingly creative, inspirational scientist,” Dr. Gitler said. “She set up a wonderful scientific environment. Even though she's gone, I still think of her every day and try my best to live up to the example she set as a scientist and as a mentor.”

In the 12 years since completing his fellowship at MIT, Dr. Gitler has focused his laboratory's work on the continued investigation of ataxin-2.

“We're really obsessed with ataxin-2,” he said. “Other new genes have been discovered in the field; we're also trying to learn about them. But we're continuing to push ahead with our primary focus on ataxin-2.”

To this day, Dr. Gitler said, he continues to spend much of his time in the lab, rather than his academic office.

“There's something special about the lab environment, where you're working late at night or weekends with other people,” he said. “You share a large part of your life with them. You get very close to them.”

Link Up for More Information

• Elden AC, Kim HJ, Hart MP, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS https://www.nature.com/articles/nature09320. Nature 2010; 466(7310):1069–1075.
• Becker LA, Huang B, Bieri G, et al. Therapeutic reduction of ataxin-2 extends lifespan reduces pathology in TDP-43 mice https://www.nature.com/articles/nature22038. Nature 2017; (7650): 367–371.