The relentless neurological disease amyotrophic lateral sclerosis (ALS) eventually shuts down the entire body, but the devastation starts at a molecular level. Over the years, researchers have linked ALS, also called Lou Gehrig’s disease, to a handful of proteins that don’t function properly because of genetic mutations. Over time, these distorted or “misfolded” proteins can clump together in the brain and nervous system, potentially gumming up normal nerve function and starting the slow march to total paralysis. In theory, it might be possible to stop the disease by repairing and preserving these proteins—a possibility that has inspired ongoing experiments and tantalizing findings in the lab of Meredith Jackrel, PhD, assistant professor of chemistry.
Neurological diseases may seem like an unusual area of research for a chemist, but Jackrel’s expertise with the structure and function of proteins has put her in position to make real progress against ALS. Last month she received a grant from the National Institutes of Health (NIH) worth nearly $430,000 to further her research into Matrin-3, a poorly understood protein that appears to play a pivotal role in some cases of ALS and frontotemporal dementia (FTD), a type of dementia caused by damage to the neurons in the frontal and temporal lobes of the brain.
“There have been very few papers on Matrin-3,” Jackrel said. “It’s been very understudied. We want to understand its intrinsic properties and how it might be disrupted in ALS and FTD.”
The grant will help Jackrel build on previous work that suggests a potential way forward in the fight against ALS. In a March 2022 paper published in the journal iScience, she and her team developed a new system to study Matrin-3 in yeast, an organism that naturally produces many of the same proteins found in humans. Experiments showed that clumps of misfolded Matrin-3 were toxic to yeast, and using this system they uncovered several key features that dictate how Matrin-3 functions and how genetic mutations can disrupt these functions. They also went on to show that engineered variants of the enzyme Hsp104 can successfully reverse the misfolding and break up the clumps, rendering the proteins harmless to the growing yeast. The results suggest that the fundamental underpinnings for ALS might be reversible, a tantalizing prospect that warrants much further investigation. “We’re very excited about the possibilities,” Jackrel said.