Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study identifies possible mechanism for brain damage in Huntington's disease

06.10.2006
Mutant huntingtin protein may block production of factor key to energy metabolism

Researchers from the MassGeneral Institute for Neurodegenerative Disease (MIND) have identified a possible mechanism underlying how the gene mutation that causes Huntington's disease (HD) leads to the degeneration and death of brain cells.

In the Oct. 6 issue of Cell, they show that the abnormal form of the huntingtin protein, the product of the HD gene mutation, interferes with the production of a protein critical to cellular energy metabolism. The discovery is the first to bring together two processes believed to be involved in the pathology of HD – the conversion of genetic information into proteins and the production of energy within cells.

"Our study indicates that these two pathogenic mechanisms are linked, in that disruption of gene transcription by mutant huntingtin leads to abnormal energy metabolism, which affects energy-dependent cellular processes and results in neurodegeneration," says Dimitri Krainc, MD, PhD, of MIND and the MGH Department of Neurology, who led the research team. "The role of mitochondria [subcellular structures that produce the cells' energy] in the process of nerve cell dysfunction and death is an emerging theme in neurodegenerative disorders, but the mechanism behind HD has been elusive."

HD causes the degeneration and death of cells in the basal ganglia – an area deep within the brain – particularly in a structure called the striatum. Although the precise function of the huntingtin protein is still unknown, recent studies have suggested that the mutant form directly interferes with transcription of neuronal genes. Evidence also has pointed to disruptions in cellular energy metabolism as key factors in HD. As a result, the MIND team focused on a protein called PGC-1a, which is known to regulate energy in cells throughout the body. Their previous research had shown that mice in which the PGC-1a gene had been knocked out developed brain lesions in the striatum.

To investigate the possible effect of the HD mutation on PGC-1a, the researchers first examined brain tissue samples from presymptomatic HD patients and found that levels of the protein were significantly reduced in the portion of the striatum first affected by the disorder. Examination of the brains of PGC-1a knockout mice found decreased activity in metabolic pathways known to be involved in mitochondrial function – pathways also downregulated in human HD – and brain samples from HD patients also showed reduced expression of mitochondrial genes.

Within the striatum HD causes degeneration of medium spiny neurons, the most common cells within the structure. The reseachers found that PGC-1a levels in those particular neurons were much lower among mice with the HD mutation than in normal mice. In contrast, levels of the protein were dramatically higher in striatal cells not affected by HD, suggesting that PGC-1a may protect against neurodegeneration. Analysis of striatal cells from the HD mice also showed significant underexpression of both PGC-1a and key mitochondrial genes, further linking decreased protein levels with deficits in energy metabolism.

Additional experiments indicated that mutant huntingtin interferes with the production of PGC-1a by occupying the regulatory region of the PGC-1a gene and inhibiting its transcription. Delivery of a viral vector expressing PGC-1a into the striatum of mice with the HD mutation resulted in significantly less degeneration of neurons that expressed the injected PGC-1a than of other striatal cells, suggesting that it may be possible to restore the protein's protective effects.

"Our work provides specific, mechanistic evidence that energy deficits contribute to neuro-degeneration in HD and suggests that enhancing energy production in the brain may be neuroprotective. We are beginning to search for new compounds that could correct PGC-1a dysregulation and potentially reverse the disruption of energy metabolism in HD," says Krainc, who is an assistant professor of Neurology at Harvard Medical School.

Sue McGreevey | EurekAlert!
Further information:
http://www.mgh.harvard.edu/

More articles from Studies and Analyses:

nachricht Real-time feedback helps save energy and water
08.02.2017 | Otto-Friedrich-Universität Bamberg

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Microhotplates for a smart gas sensor

22.02.2017 | Power and Electrical Engineering

Scientists unlock ability to generate new sensory hair cells

22.02.2017 | Life Sciences

Prediction: More gas-giants will be found orbiting Sun-like stars

22.02.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>