Unraveling Misfolded Molecules Using “Reprogrammed” Yeast Protein

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Newswise PHILADELPHIA - At the heart of brain diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease is protein misfolding, in which distorted proteins are unable to perform their normal functions. At present, there is no known way to reverse protein misfolding.

But James Shorter, Ph.D., associate professor of Biochemistry and Biophysics, at the Perelman School of Medicine, University of Pennsylvania, has found a possible way to unravel misfolded proteins by "reprogramming" Hsp104, a common yeast protein. The work was published this week in Cell.

Hsp104 is a "chaperone" protein, one that assists in the proper formation and functioning of other protein complexes. Although Hsp104 is one of the most common proteins on the planet, it has no analogue in humans or animals.

"We don't understand why animals have lost the gene for Hsp104, but at the same time, we've been wondering: Is there a therapeutic opportunity in this? asks Shorter. Can we add it back as a disruptive technology to antagonize the protein misfolding that characterizes some diseases?"

In previous studies, Shorter's lab established that the natural version of Hsp104 is active against neurodegenerative proteins such as alpha-synuclein. We expressed the wild-type protein in a rat model of Parkinsons disease and observed beneficial phenotypes," explains Shorter. But the wild-type protein just doesnt work as well as we would like."

In the present study, the team screened large libraries of Hsp104 variants to find versions that could both maintain protein structure and break up misfolded clumps. Luckily several variants came out of our screen that could suppress the toxicity associated with misfolded and clumped FUS, TDP-43, and alpha-synuclein disease proteins in yeast, while also enhancing proper protein function, he adds.

Shorter's team collaborated with the lab of Guy Caldwell at the University of Alabama to test Hsp104 variants in the worm C. elegans and found marked rescue of alpha-synuclein toxicity, the first time that engineered enzymes have been shown to suppress neurodegeneration in a multicellular animal.

"This is very exciting, as there are no agents that are known to rescue neurodegeneration and at the same time reverse protein misfolding," notes first author Meredith Jackrel, Ph.D., a postdoctoral fellow in the Shorter lab. "Certainly nobody's ever tried to reprogram an existing protein to try to accomplish that task."

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Unraveling Misfolded Molecules Using "Reprogrammed" Yeast Protein