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 Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital

nachricht Highly precise wiring in the Cerebral Cortex
21.09.2017 | Max-Planck-Institut für Hirnforschung

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: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Comet or asteroid? Hubble discovers that a unique object is a binary

21.09.2017 | Physics and Astronomy

Cnidarians remotely control bacteria

21.09.2017 | Life Sciences

Monitoring the heart's mitochondria to predict cardiac arrest?

21.09.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>