Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Regulatory enzyme overexpression may protect against neurodegeneration in Huntington's disease

19.12.2011
Mutant huntingtin protein appears to block activity of Sirt1, suggesting potential treatment target

Treatment that increases brain levels of an important regulatory enzyme may slow the loss of brain cells that characterizes Huntington's disease (HD) and other neurodegenerative disorders. In a report receiving advance online publication in Nature Medicine, a Massachusetts General Hospital (MGH)-based research team reports that increased expression of Sirt1, one of a family of enzymes called sirtuins, in the brain of a mouse model of HD protected against neurodegeneration. They also identified a potential mechanism for this protective effect.

"Diseases such as Huntington's, Parkinson's and Alzheimer's disease have different causative factors, but they share common themes – such as aggregation of misfolded proteins – and a unifying endpoint, the degenerative loss of neurons," says Dimitri Krainc, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), the study's senior author. "Pharmacological targeting of Sirt1 may provide an opportunity for therapeutic development in HD and, more generally, in the neurodegenerative disorders of aging."

HD is an inherited disorder caused by a mutation in the gene for a protein called huntingtin. Deposits of the abnormal protein accumulate within the brain, causing destruction of brain cells. Symptoms of HD usually first appear in the middle years and worsen over the 10- to 30-year course of the disorder, leading to death from a variety of complications. Sirt1 is an important regulator of the activity of proteins involved in many critical functions – including energy metabolism, inflammation and stress tolerance – and recent studies have suggested it protects against the effects of several neurodegenerative diseases.

In experiments with a mouse model of HD, the researchers first showed that knocking out Sirt1 expression in the brain accelerated the appearance of HD-like pathology – such as aggregates of mutant huntingtin and increased cell damage in key areas of the brain. In contrast, a strain of HD mice in which Sirt1 was overexpressed lived longer, with significantly less neurodegeneration and huntingtin aggregation, than did HD mice in which Sirt1 expression was unaltered. Cellular experiments showed that Sirt1 overexpression directly protects neurons from the toxic effect of mutant huntingtin.

The MGH-MIND team also discovered a new target for Sirt1 activity in TORC1, a brain protein known to regulate several important neuronal genes, and found that the presence of mutant huntingtin interferes with the interaction between Sirt1 and TORC1, reducing expression of the regulated genes. In the same issue of Nature Medicine, a research team based at Johns Hopkins School of Medicine reports similar neuroprotective effects for Sirt1. Co-authored by members of Krainc's team, the Hopkins study demonstrated that mutant huntingtin inhibits the activity of Sirt1, leading to deregulation of multiple Sirt1 targets, in two additional HD mouse models.

"Development of therapeutic agents for neurodegenerative diseases requires an in-depth understanding of the mechanisms that link the underlying biology with the resulting neuronal dysfunction," says Krainc, an associate professor of Neurology at Harvard Medical School. "Developing and testing Sirt1 activators that protect against disorders like HD will require accurate information on Sirt1 activity in the normal and diseased brain. We hope our studies can contribute valuable data to that effort, which will require collaborations with NIH, with industry and with foundations such as the Cure Huntington's Disease Initiative, one of the supporters of this study."

Additional supporters of the investigation are the National Institutes of Health, the Hereditary Disease Foundation and the Glenn Foundation for Medical Research. Co-lead authors of the Nature Medicine paper are Hyunkyung Jeong, MGH-MIND, and Dena Cohen, Massachusetts Institute of Technology (MIT). Additional co-authors are Libin Cui and Joseph Mazzulli, MGH-MIND; Andrea Supinski and Leonard Guarante, MIT; Jeffrey Savas and John Yates, Scripps Research Institute; and Laura Bordone, Novartis Institutes of BioMedical Research.

Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital (www.massgeneral.org) is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $700 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, reproductive biology, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sue McGreevey | EurekAlert!
Further information:
http://www.massgeneral.org

More articles from Health and Medicine:

nachricht World first: Massive thrombosis removed during early pregnancy
20.07.2017 | Universitätsspital Bern

nachricht Therapy of preterm birth in sight?
19.07.2017 | Universitätsspital Bern

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>