Parkinson’s disease is a progressive neurodegenerative disease that begins its damaging course in the brain many years before the onset of symptoms such as tremors, muscle stiffness, and slow movements. By 2030 the number of individuals with Parkinson’s is estimated to double to 9.3 million as a result of aging populations, but medications to prevent or delay the disease are not available.
In a new finding from Harvard-affiliated Brigham and Women’s Hospital (BWH), researchers identify a link between Parkinson’s disease onset and dysfunctional activity of energy genes in the brain and identify a potential therapeutic target — the PGC-1alpha gene — to reverse this energy gene failure. This research is published in the Oct. 6 issue of Science Translational Medicine.
“We found a clear-cut deficit in expression of genes that control the energy production in cell in patients with Parkinson’s,” said Clemens Scherzer, assistant professor of neurology at Harvard Medical School, principal investigator of the Laboratory for Neurogenomics at BWH, and author of the study. “One key set of genes dysfunctional in the brains of Parkinson’s patients is controlled by the master switch PGC-1alpha. PGC-1alpha activates mitochondrial genes, including many of those needed to maintain and repair the power plants in the mitochondria. Reduced expression of the genes that PGC-1alpha regulates likely occurs during the initial stages of Parkinson’s disease, perhaps even before the onset of symptoms.”
The researchers then showed that PGC-1alpha can be used as a “power switch” to turn on the expression of the energy genes — which are deactivated in patients with Parkinson’s — in cell models of the disease.
Targeting the PGC-1alpha gene may be a worthwhile endeavor. Pharmaceutical companies are already working on therapeutics that activate the PGC-1alpha pathway for more widespread diseases such as diabetes. This may jump-start the development of new Parkinson’s medicines.
To identify the dysfunctional processes in brains and dopamine neurons of patients with Parkinson’s, the researchers used an innovative systems biology approach. Instead of looking at individual genes separately, systems biology looks at groups of genes — or gene sets — that together program vital cellular functions.
Using this approach the international consortium of researchers scanned the activity of 522 gene sets in 410 tissue samples from deceased Parkinson’s patients. The research team was able to identify 10 gene sets that are associated with Parkinson’s disease. All 10 are responsible for cellular processes related to mitochondrial function and energy production.
“The most exciting result from our study for me is the discovery of PGC-1alpha as a potential new therapeutic target for early intervention in Parkinson’s disease,” said Scherzer. “Much-needed drugs to slow or halt Parkinson’s disease will have the greatest benefit for patients if they are given early on, before too many dopamine neurons die. If these synergies convince big pharmacy companies to pay more attention to developing therapies for Parkinson’s disease, this could be a huge benefit for patients.”
Some materials and information presented in this report were provided by the American Association for the Advancement of Science (AAAS).