Brown professors take novel approach in researching ALS, aberrant genetic mutations

PROVIDENCE – Six years ago, none of the five Brown University researchers with a major new grant from the ALS Finding a Cure Foundation had even worked on amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. That’s exactly why the team has a unique approach for making much-needed progress against the untreatable neurodegenerative disease.

Their strategy is no one’s idea of the natural next step in conventional ALS research. What makes their effort worth a shot is that the team brings together the diverse scientific brain trust needed to try something quite different. In decades of work in neuroscience and molecular biology, they have developed the needed expertise by working on other things.
“We came to this independently,” said team member Justin Fallon, professor of neuroscience.
So what’s the big idea? In a nutshell, they hope to uncover therapeutically actionable intelligence in the battle against ALS by finding rare, random cases in which genetics also derail the disease. Some genetic mutations harm us – there are about 50 mutations associated with ALS – but some mutations can help. The premise of the research – and the team’s initial results directly support this – is that there are “suppressor mutations” that end up protecting motor neurons from dying and muscle from falling apart even when an organism has a gene for ALS.
The team screens for these suppressor mutations by engineering key human ALS genes into fruit flies and C. elegans worms. Then they breed them by the million. Those few that manage to thrive despite their purposely tainted lineage are the ones lucky enough to have acquired potential suppressor mutations.
Working with two colleagues from Massachusetts, the team will pit the suppressor mutations that work in both the fly and the worm against ALS genes not only in the mouse, but also in human stem cells that have been turned into motor neurons. If all goes well, within a few years, they’ll see human motor neurons with ALS genes resisting the disease because they’ll also have a suppressor mutation found by the team.
“Our argument is that others may be working individually on these different species,” said Diane Lipscombe, professor of neuroscience and director of the Brown Institute for Brain Science, “but there is no team working together, sharing all the information and then going across these different species to ask if we identify a suppressor in a fly does it also act as a suppressor in a mouse and does it also act as a suppressor in human cell culture work?”
It’s a completely unbiased approach, Lipscombe adds. Rather than trying to guess what mutations might counteract ALS, they are letting the randomness of mutation show them. They’ll build on whatever results show promise.
Along the way, in all those diverse models, the team expects to make many key findings about the molecular mechanisms by which ALS kills motor neurons and weakens muscle and by which suppressor mutations prevent that damage. They’ll probe the electrical and physiological properties of motor neurons and their junctions with muscle. They’ll track the progression of the disease in behaving flies, worms and mice, and look for the earliest possible signs of disease.
That knowledge about how ALS and suppressor mutations work could lead to a therapy. Nine in 10 ALS cases have no clear genetic cause, Fallon said. It seems likely, though hardly certain, that whenever the disease arises, it will share the same downstream flaws in gene expression, protein-making or cell function. The scientists believe that, as they gain an understanding of those pathways of biological action common to their diverse models of the disease, and as they see how suppressor mutations counteract those, they’ll gain a clearer sense of how to intervene.
“The hope is to identify pathways that one can then target drugs to,” said Kristi Wharton, professor of biology.
Already advancing
Although the team can’t reveal too much in advance of peer-reviewed publication, subsequent analysis appears to show at least one suppressor mutation that protects flies against multiple ALS genes.
If that result holds up to further analysis, the rest of the plan kicks in. The group will crosscheck its performance in the worms, then the mice and then the human cells. Along the way, it will study the differences in gene expression, molecular pathways, electrophysiology and whole-animal behavior and progression in ALS models, with and without the suppressor gene.
It’s a huge effort that, to date, has involved dozens of professors, postdoctoral researchers, and graduate and undergraduate students. But the chance to make progress against the tragedy of ALS, which affects thousands of people in the United States alone, and to learn new biology is energizing, team members say.

“We all got incredibly motivated by the problem,” Lipscombe said. “We were, to a person, fixated on thinking this is like a race because of the rapid degeneration of people with ALS. What can we contribute?”
For now, they are contributing a new strategy. But if that pans out, they’ll have contributed a whole new way to find a cure.

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