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In Parkinson's disease, brain cells abandon mitochondria

08.10.2010
In a study that sheds new light on the causes of Parkinson's disease, researchers report that brain cells in Parkinson's patients abandon their energy-producing machinery, the mitochondria. A shutdown in fuel can have devastating effects on brain cells, which consume roughly 20 percent of the body's energy despite making up only 2 percent of body weight.

The findings indicate that boosting the mitochondria with FDA approved drugs early on may prevent or delay the onset of Parkinson's. The study will be published in the one-year anniversary issue of the journal Science Translational Medicine, on Wednesday October 6 2010. Science Translational Medicine is published by AAAS, the nonprofit science society.

Affecting roughly 5 million people worldwide, Parkinson's disease is a relentless condition that starts killing dopamine neurons in the brain many years before the onset of hallmark symptoms like tremors, muscle rigidity and slow movements. Thus, much-needed drugs to slow or halt the disease would have the greatest benefit for patients if they are given early on, before too many dopamine neurons die.

Clemens Scherzer from Brigham and Women's Hospital and Harvard Medical School, along with an international team of researchers, now show that a root cause of Parkinson's disease may lie in 10 gene sets related to energy production that spur neurons in the brain to "divorce" their mitochondria and related energy-producing pathways.

These gene sets are controlled by a master regulator—the PGC-1alpha gene. Moreover, abnormal expression of these genes likely occurs during the initial stages of Parkinson's disease, long before the onset of symptoms, the study shows. Targeting PGC-1alpha may thus be an effective way to slow down or halt the earliest stages of Parkinson's, staving off permanent damage and neuronal loss.

"The most exciting result from our study for me is the discovery of PGC-1alpha as a new therapeutic target for early intervention in Parkinson's disease. PGC-1alpha is a master switch that activates hundreds of mitochondrial genes, including many of those needed to maintain and repair the power plants in the mitochondria," Scherzer said.

FDA-approved medications that activate that PGC-1alpha are already available for widespread diseases like diabetes. These medications may jumpstart the development of new Parkinson's drugs; instead of having to start from scratch, pharmaceutical companies may be able to dust off their drug libraries and find look-alike drugs capable of targeting PGC-1alpha in the brain.

"As we wrap up our first year of publishing the journal, the new study from Zheng et al. exemplifies the goal of Science Translational Medicine, applying knowledge and technology from different fields-such as neuroscience, genomics and bioinformatics-to achieve new discoveries," said Editor Katrina Kelner.

Previous studies have linked defects in mitochondrial activity to Parkinson's disease, but they generally have not provided such a comprehensive, specific set of genes as Scherzer and colleagues now report. The researchers analyzed a part of the brain called the substantia nigra in 185 tissue samples from deceased Parkinson's patients.

The substantia nigra (Latin for "black substance") contains dopamine-producing neurons. Scherzer and colleagues used a laser beam to precisely cut out the dopamine neurons that are abnormal in Parkinson's. Next, the team looked at gene activity in these dopamine neurons and identified gene sets—groups of genes involved in one biological process—that are associated with Parkinson's disease. At the end of this tour-de-force analysis, 10 gene sets linked to Parkinson's emerged. All of these gene sets had a common thread—the master regulator gene PGC-1alpha.

The 10 gene sets encode proteins responsible for cellular processes related to mitochondrial function and energy production. Suppressing these genes is likely to severely damage components required for brain energy metabolism. One of these components is the electron transport chain; a set of reactions controlled by mitochondria that generates the energy cells need to function. Other studies have hinted that one of the five complexes making up the electron transport chain malfunctions in Parkinson's. Yet, Scherzer and colleagues found that not just one, but virtually all of the components needed by mitochondria to build the electron transport chain are deficient.

Why would the brain, being so highly energy dependent, abandon its entire energy-producing apparatus? That seems to be the core mystery of Parkinson's disease. Some think that mitochondrial activity may be affected by a combination of genes and the environment.

"I believe that environmental chemicals, risk genes, and aging—each having a small effect when taken separately—in combination may lead to the pervasive electron transport chain deficit we found in common Parkinson's disease and to which dopamine neurons might be intrinsically more susceptible," said senior author Clemens Scherzer, Assistant Professor of Neurology at Harvard Medical School.

Science Translational Medicine launched October 7 2009, as new journal in the Science family of journals intended to help speed basic research advances into clinics and hospitals. Serving scientists from academia and industry, as well as doctors, regulators and policy-makers, the journal aims to help researchers more efficiently access and apply new findings from many different fields.

This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the Maximillian E. & Marion O. Hoffman Foundation, the RJG Foundation and the Michael J. Fox Foundation.

The American Association for the Advancement of Science (AAAS) is the world’s largest general scientific society, and publisher of the journal, Science (www.sciencemag.org) as well as Science Translational Medicine (www.sciencetranslationalmedicine.org) and Science Signaling (www.sciencesignaling.org). AAAS was founded in 1848, and includes some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of 1 million. The non-profit AAAS (www.aaas.org) is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, www.eurekalert.org, the premier science-news Web site, a service of AAAS.

Natasha Pinol | EurekAlert!
Further information:
http://www.aaas.org

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