PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Researchers identify potential new drug for neurodegenerative disease

2010-09-09
(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.


ELSE PRESS RELEASES FROM THIS DATE:

New study suggests changes in diagnosis and treatment of malaria

2010-09-09
LA JOLLA, CA - September 7, 2010 –A team of scientists from The Scripps Research Institute, the Genomics Institute of the Novartis Research Foundation (GNF), and the U. S. Naval Research Detachment in Peru has completed a study that could improve the efficacy of diagnosis and treatment strategies for drug-resistant malaria. In the new study—published online on September 9, 2010 by the journal Genome Research—the scientists analyzed the genomic features of a population of malaria parasites in Peru, identifying the genetic basis for resistance to a common antibiotic. Malaria ...

NIST researchers hear puzzling new physics from graphene quartet's quantum harmonies

2010-09-09
GAITHERSBURG, Md. – Using a one-of-a-kind instrument designed and built at the National Institute of Standards and Technology (NIST), an international team of researchers have "unveiled" a quartet of graphene's electron states and discovered that electrons in graphene can split up into an unexpected and tantalizing set of energy levels when exposed to extremely low temperatures and extremely high magnetic fields. Published in this week's issue of Nature,* the new research raises several intriguing questions about the fundamental physics of this exciting material and reveals ...

New sickle cell screening program for college athletes comes with serious pitfalls, experts say

2010-09-09
The Johns Hopkins Children's Center top pediatrician is urging a "rethink" of a new sickle cell screening program, calling it an enlightened but somewhat rushed step toward improving the health of young people who carry the sickle cell mutation. Beginning this fall, all Division I college athletes will undergo mandatory screening for the sickle cell trait. The program, rolled out by the National Collegiate Athletic Association (NCAA), is an attempt to prevent rare but often-lethal complications triggered by intense exercise in those who carry the genetic mutation yet ...

Liver defect likely cause of DHA deficiency in Alzheimer's patients, UCI study finds

2010-09-09
Irvine, Calif. — UC Irvine researchers have discovered that markedly depleted amounts of an omega-3 fatty acid in brain tissue samples from Alzheimer's patients may be due to the liver's inability to produce the complex fat, also contained in fish-oil supplements. Low levels of docosahexaenoic acid, or DHA, have been associated with the chronic neurodegenerative disease affecting millions of Americans, but no cause had been identified. In postmortem liver tissue from Alzheimer's patients, the UCI team found a defect in the organ's ability to make DHA from shorter molecules ...

The Economics of Ecosystems and Biodiversity (TEEB) Local and Regional Policy Makers report launched at major biodiversity conference in Ghent

The Economics of Ecosystems and Biodiversity (TEEB) Local and Regional Policy Makers report launched at major biodiversity conference in Ghent
2010-09-09
Ghent, 9 September 2010 – Factoring the planet's multi-trillion dollar ecosystem services into policy-making can help save cities and regional authorities money while boosting the local economy, enhancing quality of life, securing livelihoods and generating employment. This is the finding from a major international study, launched in a report by TEEB for Local and Regional Policy Makers, being released in Belgium, Brazil, India, Japan and South Africa. In the Framework of the Belgian Presidency of the European Union, the Flemish Ministry of Environment, Nature and ...

Unauthorized population would soar if birthright citizenship repealed

2010-09-09
University Park, Pa. -- Repeal of birthright citizenship for the U.S.-born children of unauthorized immigrants would expand the nation's unauthorized population by at least 5 million over the next decade, according to a new report from the Migration Policy Institute. The report's principal author is Jennifer Van Hook, professor of sociology and demographics at Penn State and non-resident fellow at the Washington, D.C.-based institute. "While some are discussing an end to birthright citizenship as a means to reduce illegal immigration," Van Hook said, "repeal of birthright ...

Satellite data reveal seasonal pollution changes over India

Satellite data reveal seasonal pollution changes over India
2010-09-09
CHAMPAIGN, Ill. — Armed with a decade's worth of satellite data, University of Illinois atmospheric scientists have documented some surprising trends in aerosol pollution concentration, distribution and composition over the Indian subcontinent. In addition to environmental impact, aerosol pollution, or tiny particles suspended in the air, can be detrimental to human health by causing a range of respiratory problems. Aerosols can come from natural sources, such as dust and pollen carried on the wind, but the most hazardous aerosols are generated by human activity – soot ...

Why the biological clock? Penn study says aging reduces centromere cohesion, disrupts reproduction

Why the biological clock? Penn study says aging reduces centromere cohesion, disrupts reproduction
2010-09-09
PHILADELPHIA –- University of Pennsylvania biologists studying human reproduction have identified what is likely the major contributing factor to the maternal age-associated increase in aneuploidy, the term for an abnormal number of chromosomes during reproductive cell division. Using naturally aging mouse models, researchers showed that this basic fact of reproductive life is most likely caused by weakened chromosome cohesion. Older oocytes, or egg cells, have dramatically reduced amounts of a protein, REC8, that is essential for chromosomes to segregate correctly ...

Cash hoarding nothing new for businesses, scholar says

2010-09-09
CHAMPAIGN, Ill. — The U.S. economy is experiencing anemic growth, yet businesses are sitting on a mountain of cash worth nearly $2 trillion, according to Federal Reserve estimates. But this trend is nothing new for firms, who have been steadily increasing their cash holdings over the past three decades, a University of Illinois business professor says. Finance professor Heitor Almeida says the fact that businesses are stuffing corporate piggy banks with spare cash for the proverbial "rainy day" is unrelated to the belt-tightening brought about by the continuing financial ...

Twins are intriguing research subjects for Notre Dame biometircs researchers

2010-09-09
Each year in August, the aptly named town of Twinsburg, Ohio, is the site of the largest official gathering of twins in the world. Open to all multiples — identical and fraternal twins, triplets and quads from newborns to octogenarians — the weekend's events include food, live entertainment, a golf tournament, and a twins' parade. The event also has become an important site for field research by Kevin Bowyer and Patrick Flynn of the University of Notre Dame's Department of Computer Science and Engineering. Flynn has a twin sister, making this research especially relevant ...

LAST 30 PRESS RELEASES:

Reality check: making indoor smartphone-based augmented reality work

Overthinking what you said? It’s your ‘lizard brain’ talking to newer, advanced parts of your brain

Black men — including transit workers — are targets for aggression on public transportation, study shows

Troubling spike in severe pregnancy-related complications for all ages in Illinois

Alcohol use identified by UTHealth Houston researchers as most common predictor of escalated cannabis vaping among youths in Texas

Need a landing pad for helicopter parenting? Frame tasks as learning

New MUSC Hollings Cancer Center research shows how Golgi stress affects T-cells' tumor-fighting ability

#16to365: New resources for year-round activism to end gender-based violence and strengthen bodily autonomy for all

Earliest fish-trapping facility in Central America discovered in Maya lowlands

São Paulo to host School on Disordered Systems

New insights into sleep uncover key mechanisms related to cognitive function

USC announces strategic collaboration with Autobahn Labs to accelerate drug discovery

Detroit health professionals urge the community to act and address the dangers of antimicrobial resistance

3D-printing advance mitigates three defects simultaneously for failure-free metal parts 

Ancient hot water on Mars points to habitable past: Curtin study

In Patagonia, more snow could protect glaciers from melt — but only if we curb greenhouse gas emissions soon

Simplicity is key to understanding and achieving goals

Caste differentiation in ants

Nutrition that aligns with guidelines during pregnancy may be associated with better infant growth outcomes, NIH study finds

New technology points to unexpected uses for snoRNA

Racial and ethnic variation in survival in early-onset colorectal cancer

Disparities by race and urbanicity in online health care facility reviews

Exploring factors affecting workers' acquisition of exercise habits using machine learning approaches

Nano-patterned copper oxide sensor for ultra-low hydrogen detection

Maintaining bridge safer; Digital sensing-based monitoring system

A novel approach for the composition design of high-entropy fluorite oxides with low thermal conductivity

A groundbreaking new approach to treating chronic abdominal pain

ECOG-ACRIN appoints seven researchers to scientific committee leadership positions

New model of neuronal circuit provides insight on eye movement

Cooking up a breakthrough: Penn engineers refine lipid nanoparticles for better mRNA therapies

[Press-News.org] Researchers identify potential new drug for neurodegenerative disease