Parkinson’s disease pathology breakthrough

By Dr. Ananya Mandal, MDOct 8 2010

Researchers have found that brain cells of people with early Parkinson's disease have damaged powerhouses. In a new study they have identified 10 groups of gene sets related to the energy production problems in the brain cells of these people.

Parkinson’s diseases is a debilitating and degenerative brain disease that progresses slowly, leading to resting tremors on one side of the body, slow movements, rigidity and gait or balance problems. There has been earlier evidence that damage to the mitochondria- that are the powerhouses of the cells may contribute to neurological damage in Parkinson's. A pesticide called rotenone produces similar symptoms in rats, and interferes with electron transport in mitochondria, which is vital to generate energy in cells. In the latest study it was seen that some patients have a rare inherited form of Parkinson's that carries mutations in genes that regulate mitochondria.

The research team found that the 10 gene sets in question are controlled by a master regulator called the PGC-1alpha gene, which the study's authors surmise might be a root cause of the disease. These genes also determine the early course of the disease.

The findings appear in this week's issue of Science Translational Medicine.

Neurologist Clemens Scherzer from Brigham and Women's Hospital and Harvard Medical School in Boston and his co-authors write, “This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs.” Scherzer said there may be multiple factors associated with the disease including environmental chemicals, risk genes and ageing. These, he explained may work in combination to lead to the electron transport chain deficit found in Parkinson's. He explained, “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.”

For the study the researchers used an innovative systems biology approach. They looked at gene sets that together program vital cellular functions. They scanned the activity of 522 gene sets in 410 tissue samples from deceased Parkinson's patients.  “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. 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,” says Scherzer.

Some of the drugs that activate the PGC-1alpha gene already have been approved by the U.S. Food and Drug Administration for treatment of other diseases, such as Type 2 diabetes. This may open up new avenues in Parkinson’s disease therapy.

The study was funded by the U.S. National Institute of Neurological Disorders and Stroke, the U.S. National Institute on Aging, the Maximillian E. & Marion O. Hoffman Foundation, the RJG Foundation and the Michael J. Fox Foundation.