Researchers identify potential new drug for neurodegenerative disease

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Researchers identify potential new drug for neurodegenerative disease

http://www.eurekalert.org/pub_releases/2010-09/hms-rip090710.php

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, Creutzfeldt Jakob 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 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.

###

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 & .

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), Gartner (1)(5), Nevena Dimova

(1), Hanna (1)(6), P. Gygi (1), M. (4), Randall W. King

(1)(8), and 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, 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.

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