(Press-News.org) BOSTON, Mass. (September 8, 2010)‹Scientists have discovered a small
molecule that helps human cells get rid of the misfolded, disfigured
proteins implicated in Alzheimer¹s disease and other neurodegenerative
ailments. This potential drug could have applications for other conditions
as well.
Cells create and discard proteins continuously, a process that relies on a
balance between the speed with which new proteins are created and damaged
ones destroyed. Protein destruction occurs through a sophisticated system
that marks proteins for disposal by tagging them with a small molecule
called ubiquitin. Ubiquitin latches onto these proteins, often forming long
chains. The cell¹s protein waste-disposal system, the proteasome, recognizes
these ubiquitinated proteins and breaks them down.
If that finely tuned system malfunctions, damaged or misfolded proteins
begin to accumulate in the cell and may become toxic. A number of ailments,
including Parkinson¹s, CreutzfeldtJakob and Alzheimer¹s have been linked to
this build up of misfolded proteins.
To better understand just what causes this malfunction, a research team led
by Harvard Medical School researchers Daniel Finley, professor of cell
biology, and Randall King, associate professor of cell biology, zeroed in on
an enzyme called Usp14. They found that, when activated, Usp14 disassembles
the ubiquitin chain, slowing down the proteasome¹s ability to rid the cell
of bad proteins. As a result, the cell makes new proteins faster than it
rids 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 inhibited
Usp14, thus allowing the proteosome to work effectively. To identify such a
selective inhibitor, Byung-Hoon Lee, a postdoctoral researcher, developed a
special screening assay with assistance from the Institute of Chemistry and
Cell Biology-Longwood Screening Facility at HMS. Lee screened 63,000
compounds, looking for molecules that inhibited only Usp14 and could easily
infiltrate the cell. The strongest candidate was a small molecule they named
IU1.
Experimenting in both human and mouse cell cultures, Min Jae Lee, also a
postdoctoral researcher, and his coworkers found that IU1 inhibited Usp14
and allowed the proteasome to dispose of proteins more quickly. In other
words, adding IU1 to cells boosted proteasome activity.
Though scientists are still investigating just how IU1 works, it appears
that the molecule suppresses Usp14¹s ability to trim the ubiquitin chain.
In addition to discovering IU1, this research has also shed light on an
aspect of proteasome function that was not previously understood, King says.
Scientists had thought that the proteasome was not involved in regulating
the speed of protein degradation, but that other proteins work with
ubiquitin to modulate the process. ³Our work suggests that there is another
level of control where the rate at which the proteasome can degrade these
ubiquinated proteins is also controlled,² King says. ³It looks like there
are multiple control steps along the way in this pathway.²
As scientists learn more about the link between misfolded proteins and human
disease, interest in the proteasome has increased. While much of that focus
has been on ways to inhibit proteasome function, there may be an advantage
to 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 proteasome
activity, it would immediately die.²
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, King says.
For example, when a cell suffers oxidative damage‹say from a stroke or heart
attack‹proteins may fold improperly and be marked for degradation by the
ubiquitin system. If the proteasome becomes overwhelmed, misfolded proteins
could accumulate in the cell, triggering a cascade of problems. In this
latest study, researchers induced protein oxidation in cells and then
treated them with IU1, which resulted in rapid elimination of the oxidized
proteins. At the same time, the ability of cells to survive oxidative insult
was enhanced.
INFORMATION:
Patents are pending for IU1 and the assay used to identify the molecule.
This research was funded by the National Institutes of Health, Harvard
Technology Development Accelerator Fund, Merck & Co., and Johnson & Johnson.
Written by Kelli Whitlock Burton.
Full citation
Nature, Volume 467, issue 7312, pp 179-184
³Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14²
Byung-Hoon Lee (1)(7), Min Jae Lee (1)(7), Soyeon Park (1), Dong-Chan Oh
(2)(3), Suzanne Elsasser (1), Ping-Chung Chen (4), Carlos Gartner (1)(5),
Nevena Dimova (1), John Hanna (1)(6), Steven P. Gygi (1), Scott M. Wilson
(4), Randall W. King (1)(8), and Daniel Finley (1)(8)
(1) Department of Cell Biology, Harvard Medical School, 240 Longwood Ave,
Boston, MA 02115, USA
(2) Department of Biological Chemistry and Molecular Pharmacology, Harvard
Medical School, 240 Longwood Ave, Boston, MA 02115, USA
(3) Natural Products Research Institute, College of Pharmacy, Seoul National
University, San 56-1, Sillim, Seoul 151-742, Republic of Korea
(4) Department of Neurobiology, Evelyn F. McKnight Brain Institute, Civitan
International Research Center, University of Alabama at Birmingham,
Birmingham, AL 35294, USA
(5) Present address: Department of Biological Sciences, 193 Galvin Life
Sciences Center, Notre Dame, IN 46556, USA
(6) Present address: Department of Pathology, Brigham and Women's Hospital,
75 Francis Street, Boston, MA 02115, USA
(7) These authors contributed equally to this work.
Harvard Medical School (http://hms.harvard.edu/hms/home.asp) has more than
7,500 full-time faculty working in 11 academic departments located at the
School's Boston campus or in one of 47 hospital-based clinical departments
at 17 Harvard-affiliated teaching hospitals and research institutes. Those
affiliates include Beth Israel Deaconess Medical Center, Brigham and Women's
Hospital, Cambridge Health Alliance, Children's Hospital Boston, Dana-Farber
Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew
SeniorLife, Joslin Diabetes Center, Judge Baker Children's Center,
Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, McLean
Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding
Rehabilitation Hospital, and VA Boston Healthcare System.
Researchers identify potential new drug for neurodegenerative disease
2010-09-09
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