Harvard Medical School Researchers Discover Molecule

Researchers at Harvard Medical School recently discovered a small molecule that may revolutionize the treatment of several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Creutzfeldt-Jacob.

Daniel Finley, professor of cell biology, and Randy King, associate professor of cell biology, discovered that the enzyme called USP14 accelerates the buildup of damaged or misfolded proteins, which can cause cell toxicity and lead to certain neurodegenerative diseases.

USP14 removes a ubiquitin tag from proteins marked for degradation and thus prevents them from being cleared by the proteasome, which breaks down proteins, according to Byung-Hoon Lee, a postdoctoral research fellow and lead author of the paper.

“We found that the USP14 enzyme is an endogenous inhibitor for the proteasome,” Lee said. “Then we asked: how can we suppress this inhibitor to possibly enhance the proteasome function?”

Lee said that he and his colleagues screened more than 63,000 small molecules that they hypothesized might inhibit USP14. Of these, they advanced one that showed the strongest results—termed IU1—into further testing.

The researchers observed that IU1 enabled the proteasome to clear and degrade toxic proteins—like the tau protein, which is central to Alzheimer’s disease—more quickly.

“The biggest implication of this research is that it is possible to accelerate the degradation of proteins in cells,” King said. “We can enhance cell survival or cell behavior if we can enable the cell to dispose of these proteins more quickly.”

Lee said that the USP14 inhibitor molecule, IU1, is a promising drug candidate because it effectively activates the proteasome and is relatively stable in the cell.

The researchers may collaborate with biotechnology companies to perform in-vivo tests of IU1. They also hope to modify the molecule to see if modifications might improve its potency or stability, according to Lee.

The findings were published early Sept. in Nature.