In a quiet chemistry lab at Washington University in St. Louis, researchers have cracked open a faster path to fighting two of neuroscience's most stubborn opponents: the misfolded proteins that destroy nerve cells in ALS and Parkinson's disease. Meredith Jackrel, an associate professor of chemistry, and her team have developed a method to rapidly screen thousands of engineered enzymes—molecules that could one day help reverse the devastating protein clumps that define these diseases.
The breakthrough centers on Hsp104, a disaggregase enzyme naturally produced by yeast to survive heat stress. The enzyme works like a molecular crowbar: it can break apart and untangle the tangled protein aggregates that accumulate in the brains and spinal cords of people with neurodegenerative disease. Specifically, Jackrel's team focused on how Hsp104 could dissolve TDP-43, a misfolded protein that clumps in people with ALS, and α-synuclein, which accumulates in Parkinson's patients. Even more promising, the enzyme can help these proteins refold into healthy configurations, potentially restoring normal cell function.
The real innovation isn't Hsp104 itself—it's how the team finds improved versions of it. Traditionally, identifying better variants was brutally slow. Researchers would introduce mutations into Hsp104, let yeast colonies grow on a plate, pick them up one by one with a toothpick, and then analyze them using DNA sequencing. This method allowed analysis of only a few hundred versions at a time. "Previous methods for producing and identifying them were extremely slow and tedious," Jackrel said of disaggregases. "Our new method is a significant step forward."
The new approach flips that paradigm entirely. Instead of analyzing colonies one-by-one, Jackrel's team—including lead author Jeremy Ryan, now at Bayer, and graduate students Madalyn Bochantine, Karlie Miller, and April Lopez—creates tens of millions of variations simultaneously. They introduce many different mutations into a single region of Hsp104, generating a vast library of possibilities. Then they deploy deep sequencing, a highly sensitive technology that reads millions of DNA fragments at once, to identify which engineered versions work best at breaking down misfolded proteins.
"We can essentially look at the entire population at once and see which versions of Hsp104 work well in some situations and not in others," Jackrel explained. The new engineered variants that emerged from this screening process have characteristics that make them more promising than earlier known versions.
The timing matters. TDP-43 is already a top target for scientists and pharmaceutical companies worldwide, because it's implicated not just in ALS but also in dementia and certain forms of Alzheimer's disease. Yet so far, no drugs have successfully cleared the protein or slowed disease progression. "We know that buildups of misfolded TDP-43 and α-synuclein are important in the development of neurodegenerative disease," Jackrel noted, "so anything that can reverse that buildup could be helpful."
The path from lab to clinic remains long. Jackrel acknowledged that years of further experiments and refinement lie ahead before Hsp104 could become a clinical therapy. But the speed with which researchers can now discover improved enzymes collapses timelines that were once measured in years into months. "Hsp104 could be part of the answer," Jackrel said, "so this is a major accomplishment for our team." The work, published in Molecular Cell, opens a much faster route to testing whether engineered disaggregases belong in the toolkit against diseases that have so far eluded treatment.