Researchers at Harvard Medical School have discovered a molecule that helps human cells get rid of the misfolded, disfigured proteins implicated in Alzheimer’s disease and other neurodegenerative ailments.

This study could have far-reaching implications for the development of drugs to treat not only neurodegenerative diseases but also other illnesses that have been linked to an accumulation of bad proteins.

Cells are continuously creating and discarding proteins, a process that depends on the precious balance between the speed in which new proteins are created and the rate at which damaged ones are destroyed.

Protein destruction is part of this sophisticated system and proteins are marked as garbage by being tagged with a small molecule called ubiquitin.

Ubiquitin fastens onto these marked proteins, often forming long chains. Then the cell’s protein garbage-disposal system, the proteasome, recognizes these ubiquitinated proteins and breaks them down.

If this finely-tuned system malfunctions, damaged or misfolded proteins begin to accumulate in the cell and may become toxic. A number of ailments, including Alzheimer’s , Parkinson’s and Creutzfeldt–Jakob have been associated with this buildup of misfolded proteins.

A research team led by Harvard Medical School researchers Daniel Finley, professor of cell biology, and Randall King, associate professor of cell biology, wanted to better understand just what causes this system to malfunction.  So they honed in on an enzyme called Usp14.

During their research, scientists discovered that Usp14, when activated, breaks apart the ubiquitin chain.  This slows down the proteasome’s ability to rid the cell of bad proteins. When this happens, the cell creates new proteins faster than it gets rid of the old ones, leading to a build-up of disfigured proteins.

The researchers set out to see if they could then find a molecule that blocked Usp14—a selective inhibitor—which would allow the proteosome to freely do its job.

In order to find this selective inhibitor, Byung-Hoon Lee, a postdoctoral researcher, created a unique screening process with assistance from the Institute of Chemistry and Cell Biology-Longwood Screening Facility at HMS.

Lee screened 63,000 compounds, searching for molecules that inhibited only Usp14 and could easily infiltrate the cell. The strongest candidate was a small molecule they named IU1.

Another postdoctoral researcher, Min Jae Lee, and his coworkers put IU1 to work in both human and mouse cell cultures.  They found that IU1 inhibited Usp14 while also allowing the proteasome to get rid of bad proteins more quickly. So adding IU1 to cells actually boosted proteasome activity.

Though scientists are still trying to figure out just how IU1 works, it seems that the molecule holds back Usp14’s ability to trim the ubiquitin chain.

As scientists learn more about the connection between disfigured proteins and human disease, interest in the proteasome has increased. While much of that focus has been on ways to slow down proteasome activity, there may be a unique advantage to a drug that boosts proteasome activity rather than hinders it, Finley said.

“If you take a typical cell growing in culture and kill its Usp14 activity, the cell will continue to thrive,” said Finley. “If you kill its proteasome activity, it would immediately die.”

This research could have far-reaching implications for the development of drugs to treat not only neurodegenerative diseases, but also other illnesses that have been linked to an accumulation of misfolded proteins, said King.

Source: Harvard Medical School