BOSTON, Mass. (September 8, 2010)‹Scientists have discovered a smallmolecule that helps human cells get rid of the misfolded, disfiguredproteins implicated in Alzheimer¹s disease and other neurodegenerativeailments. This potential drug could have applications for other conditionsas well.
Cells create and discard proteins continuously, a process that relies on abalance between the speed with which new proteins are created and damagedones destroyed. Protein destruction occurs through a sophisticated systemthat marks proteins for disposal by tagging them with a small moleculecalled ubiquitin. Ubiquitin latches onto these proteins, often forming longchains. The cell¹s protein waste-disposal system, the proteasome, recognizesthese ubiquitinated proteins and breaks them down.
If that finely tuned system malfunctions, damaged or misfolded proteinsbegin to accumulate in the cell and may become toxic. A number of ailments,including Parkinson¹s, CreutzfeldtJakob and Alzheimer¹s have been linked tothis build up of misfolded proteins.
To better understand just what causes this malfunction, a research team ledby Harvard Medical School researchers Daniel Finley, professor of cellbiology, and Randall King, associate professor of cell biology, zeroed in onan enzyme called Usp14. They found that, when activated, Usp14 disassemblesthe ubiquitin chain, slowing down the proteasome¹s ability to rid the cellof bad proteins. As a result, the cell makes new proteins faster than itrids itself of the old ones, leading to a build-up of misfolded proteins.
The researchers wanted to see if they could find a molecule that inhibitedUsp14, thus allowing the proteosome to work effectively. To identify such aselective inhibitor, Byung-Hoon Lee, a postdoctoral researcher, developed aspecial screening assay with assistance from the Institute of Chemistry andCell Biology-Longwood Screening Facility at HMS. Lee screened 63,000compounds, looking for molecules that inhibited only Usp14 and could easilyinfiltrate the cell. The strongest candidate was a small molecule they namedIU1.
Experimenting in both human and mouse cell cultures, Min Jae Lee, also apostdoctoral researcher, and his coworkers found that IU1 inhibited Usp14and allowed the proteasome to dispose of proteins more quickly. In otherwords, adding IU1 to cells boosted proteasome activity.
Though scientists are still investigating just how IU1 works, it appearsthat the molecule suppresses Usp14¹s ability to trim the ubiquitin chain.
In addition to discovering IU1, this research has also shed light on anaspect of proteasome function that was not previously understood, King says.Scientists had thought that the proteasome was not involved in regulatingthe speed of protein degradation, but that other proteins work withubiquitin to modulate the process. ³Our work suggests that there is anotherlevel of control where the rate at which the proteasome can degrade theseubiquinated proteins is also controlled,² King says. ³It looks like thereare multiple control steps along the way in this pathway.²
As scientists learn more about the link between misfolded proteins and humandisease, interest in the proteasome has increased. While much of that focushas been on ways to inhibit proteasome function, there may be an advantageto developing a drug that boosts proteasome activity rather than hinders it,Finley speculates.
³If you take a typical cell growing in culture and kill its Usp14 activity,the cell will continue to thrive,² he says. ³If you kill its proteasomeactivity, it would immediately die.²
This research could have far-reaching implications for the development ofdrugs to treat not only neurodegenerative diseases, but also other illnessesthat have been linked to an accumulation of misfolded proteins, King says.
For example, when a cell suffers oxidative damage‹say from a stroke or heartattack‹proteins may fold improperly and be marked for degradation by theubiquitin system. If the proteasome becomes overwhelmed, misfolded proteinscould accumulate in the cell, triggering a cascade of problems. In thislatest study, researchers induced protein oxidation in cells and thentreated them with IU1, which resulted in rapid elimination of the oxidizedproteins. At the same time, the ability of cells to survive oxidative insultwas enhanced.
Source: Harvard Medical School