Parkinson’s disease results from the death of neurons that produce the chemical messenger dopamine, but what causes these cells to self-destruct has remained a mystery. New research points to decreased activity in a group of genes that help manage the flow of energy throughout the cell. The study suggests new therapies for treating Parkinson’s disease—one of which is already FDA-approved for diabetes—and opens up new possibilities for understanding how the disease unfolds.
The co-authors of the paper, which appeared in the Science Translational Medicine on Oct. 6, 2010, represent some 14 research centers in the United States, the United Kingdom, Denmark, Germany, Australia, and Korea. The team first performed a sweeping “meta-analysis” of previously published studies. Using rigorous statistical models to sift through the millions of reported variations in gene “expression” or activation, the researchers focused on 500 pathways or gene sets—groups of genes that encode a biological process.
The researchers included an analysis of three studies of individual dopamine-producing neurons, isolated from the brains of people with Parkinson’s disease by a technique known as laser capture. Finally, the team looked at brain tissue taken post mortem from individuals who had no symptoms, but whose brains showed changes known to be precursors of Parkinson’s.
Again and again, viewed from every angle, about 10 groups of genes emerged as “underexpressed,” or insufficiently activated. All help to keep operational the tiny power stations known as mitochondria—the small organs within a cell that generate the cell’s energy supply. Some of the underactive genes were those that help keep “free radicals” in check, thereby controlling the damage to neurons that is a feature of Parkinson’s disease, Alzheimer’s disease, and normal aging.
The malfunctioning genes are controlled by a master switch, known by its abbreviation PGC-1 alpha, which also proved to be turned down in all phases of the study. “This gene is an excellent drug target, because it controls so many of the other genes involved in energy production and because several compounds that work on it are already available,” says Clemens Scherzer, a neurologist at Harvard Medical School and Brigham and Women’s Hospital, and lead author of the study. “We wondered, what if we could turn this master switch back on?”
As part of the study, the researchers found that elevating levels of PGC-1 alpha did protect dopamine-producing neurons from the Parkinson-like damage caused by the pesticide rotenone. Scherzer and his co-workers are now studying whether pioglitazone, an FDA-approved drug for diabetes that boosts levels of PGC-1 alpha, will also work in people with Parkinson’s disease.
Scherzer adds that because the genetic changes were also seen in the brains of patients in the very earliest stages of disease, the finding could lead to ways of diagnosing the condition early. “By the time symptoms appear, up to 70 percent of the dopamine-producing neurons have been lost, and the available treatments are too little, too late,” he says.
According to James Bennett, director of the Parkinson’s Center at Virginia Commonwealth University, the study does even more than suggest a new therapeutic approach for people with Parkinson’s: It shows something is clearly going on in the brain that might explain why the disease occurs. “It’s as if the neuron is trying to divorce the mitochondria by turning off the genes that keep them functional,” he says. “The obvious question is, why?”
Neurons have more mitochondria than any other cell in the body, Bennett explains, because the brain is a greedy energy consumer—using up 20 percent of the body’s energy while accounting for only 2 percent of body weight. “There must be some reason why neurons would shut down their own energy supply,” he says. His laboratory is now examining mitochondria in both Parkinson’s disease and amyotropic lateral sclerosis (ALS, or Lou Gehrig’s disease). In the May issue of Molecular Neurodegeneration, his team showed that motor neurons of patients with ALS also show alterations in mitochondrial DNA.
Bennett describes the research by Scherzer and colleagues as a “landmark study” that will pertain to many neurodegenerative diseases as well as normal aging. He adds: “The days of the ‘lone ranger’ scientist are over. This finding couldn’t have happened without intensive cooperation among research centers around the world.”