The brain cells of patients with Parkinson's disease undergo a shutdown of their energy powerhouses, the mitochondria, according to a new study. Because this shutdown probably occurs early in Parkinson's cases, the finding could lead to therapies that stop the disease before too much damage has been done.
Researchers identified 10 groups of genes — called gene sets, each carrying out one biological process — associated with Parkinson's disease. Many of these gene sets are involved in helping the mitochondria do their job. Even in people whose autopsies revealed early Parkinson's — who did not have clinical symptoms, but whose brains showed signs of the disease — these gene sets were not expressed properly, meaning the mitochondria in those cells probably weren't working.
The loss of working mitochondria, which produce most of the cell's energy, may contribute to the onset of the disease, the researchers said.
All of these gene sets are controlled by a single gene, a "master regulator" called PGC-1alpha that switches the gene sets on or off. This gene could be a target for future therapies to treat or prevent the disease, the researchers said.
Their results are published today in the journal Science Translational Medicine.
Parkinson's affects about 5 million people globally. The disease kills brain cells that produce the chemical dopamine. This impairs patients' movements, causing symptoms such as tremors, muscle stiffness and impaired balance and coordination. The cause of the disease is not known.
Clemens Scherzer, of Brigham and Women's Hospital and Harvard Medical School, and his colleagues analyzed genetic data from 17 studies involving a total of 322 human brain tissue samples and 88 blood samples. Of these, 185 were derived from the dopamine-producing brain cells of deceased patients with Parkinson's.
They initially found 28 gene sets to be associated with Parkinson's. Further research looking into the genomes of patients with early Parkinson's narrowed the field to 10 gene sets.
Some of these gene sets contain the genetic code to make proteins involved in the electron transport chain — a set of reactions inside the mitochondria that produce energy. Defects in the electron transport chain would severely affect the ability of the brain cells to generate energy, the researchers said.
It's possible that genetic and environmental influences, along with aging, have a combined impact on the expression of the mitochondrial genes, Scherzer said.
Medications 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 diabetes. This means pharmaceutical companies may be able to develop new drugs for Parkinson's by tweaking already developed drugs rather than by starting from scratch, the researchers said.
The study was funded by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Michael J. Fox Foundation, among others.