Energy-boosting Protein May Ease Neural Oxidative Stress

Seen to Protect Brain Against Neurodegeneration

A molecule better known for turbo-charging muscles and burning fat also appears to protect mouse brains from disease and dysfunction, according to independent papers by HMS researchers.

The molecule goes by the unwieldy name of peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha, or PGC-1 alpha for short. Its complex actions can be summed up more simply: PGC-1 alpha revs up the number and activity of mitochondria when tissues need a boost.

Photo by Steve Gilbert In mouse brains, the molecule that powers up mitochondria, PGC-1 alpha, also cleans up the toxic emissions from the cellular on-demand energy system, says a new paper from researchers in the lab of Bruce Spiegelman.

Mitochondria suck up about 90 percent of the oxygen from every breath to power each cell in the body. PGC-1 alpha enables the on-demand energy system in different cells to adapt quickly and specifically to the changing demands of life. As director of mitochondrial function, PGC-1 alpha (and its close relative PGC-1 beta) delivers stamina to exercising muscles and releases life-sustaining glucose from liver cells in fasting bodies.

Ever since PGC-1 alpha and its crucial role in mitochondrial biogenesis and respiration were first identified in the lab of Bruce Spiegelman, HMS professor of cell biology at Dana–Farber Cancer Institute, many researchers have been dreaming of ways to selectively rev up the protein in fat-burning tissues to fight obesity and its health consequences.

The latest findings add the brain and neurodegenerative diseases to the list of areas that might benefit. “It almost seems like a miraculous molecule,” Spiegelman said. The loss of PGC-1 alpha may not be the root cause of the brain diseases, he said, but it seems to be part of the pathology, and stimulating the molecule may limit the damage.

The Huntington’s Link
The first hint of a relationship between PGC-1 alpha and neurodegeneration came from a knockout mouse developed to gain insight into how PGC-1 alpha regulates obesity and energy expenditure. On a high-fat diet, the knockout mice resisted the usual weight gain and insulin resistance. Part of the reason was the animals’ extra movement and higher metabolic rate, said lead investigator Jiandie Lin, then a postdoctoral fellow in Spiegelman’s lab and now an assistant professor at the University of Michigan.

Photo courtesy of Dimitri Krainc Researchers in the lab of Dimitri Krainc showed that in mice with Huntington's disease, the mutant huntingtin protein attaches to DNA upstream of the gene for PGC-1 alpha and directly interferes with transcription of this molecular director of the cellular energy system.

The hyperactivity and some of their postures, such as limb clasping, pointed researchers to the brain. A little more scientific sleuthing in collaboration with researchers in the lab of Dimitri Krainc, HMS assistant professor of neurology at Massachusetts General Hospital, revealed a veritable Swiss cheese of a deteriorating striatum in each animal. Located deep in mouse and human brains, the striatum contains the neurons that die in Huntington’s disease.

Two years later, collaborators in that project now report genetic evidence for the key role of PGC-1 alpha in a mouse model of Huntington’s disease. Knocking out the gene for PGC-1 alpha makes the Huntington’s mutation more toxic in mice. Replenishing the molecule is neuroprotective in mice with the mutant huntingtin gene, according to a paper in the Oct. 6 Cell by postdoc Libin Cui and colleagues in Krainc’s lab.

In further mechanistic findings, mutant huntingtin appears to inhibit transcription of PGC-1 alpha at a time when the cell may need it most to cope with increased energy demands and other effects of the mutation. The researchers found the mutant huntingtin protein sitting on a regulatory region of the PGC-1 alpha gene, suggesting that the mutant acts as a transcriptional co-repressor in vivo, Krainc said. PGC-1 alpha itself is a transcription cofactor that works in the nuclear genome to amplify expression of genes for mitochondrial activity. It also gangs up with molecular partners to synchronize the extra power with the customized gene expression patterns of different cell types.

In other supportive evidence, Krainc’s team found reduced expression of PGC-1 alpha in the striatum, but not other brain regions, in postmortem brain samples from presymptomatic Huntington’s disease patients.

“The identification of PGC-1 alpha as a target of mutant huntingtin could explain the early defects in energy metabolism seen in the subset of striatal neurons that eventually succumb in Huntington’s disease,” wrote Krainc in an e-mail. “We hypothesize that in the normal state, PGC-1 alpha regulates metabolic programs and maintains energy homeostasis in the central nervous system. Inhibition of PGC-1 alpha transcription by mutant huntingtin leads to defects in energy metabolism and dysfunction of neurons that are most vulnerable to metabolic stress.”

Sopping Up Toxicity
Meanwhile, researchers in Spiegelman’s lab wanted to know why more PGC-1 alpha appears to do more good than harm in most tissues. After all, more mitochondria spew out more of the major endogenous toxins in the body, known as reactive oxygen species (ROS). Scientists believe these reactive molecules contribute to aging, cancer, and cardiac damage after a heart attack. But if anything, exercise and the resulting increase in mitochondria seem associated with fewer ROS-related changes.

Reactive oxygen species have also been strongly implicated in neurodegeneration, so the team focused on two neurodegenerative conditions in mouse models of Parkinson’s disease and seizures. In the absence of PGC-1 alpha, neurological damage from oxidative insults was more severe. With the molecule, the neurons were protected.

The group’s experiments, reported in the Oct. 20 Cell, showed that PGC-1 alpha turns on nearly all the anti-ROS systems, including the first powerful line of defensive enzymes that sop up reactive oxygen. The detoxification also included more efficiently burning uncoupling proteins, which can reduce ROS production. (Inefficient uncoupling proteins make heat; the usual mitochondrial energy product is ATP, which is stored as fat if not used right away.)

“This is a broad effect that goes beyond any one model system,” Spiegelman said. “This is exciting, because apparently this is how nature wires the system to suppress ROS. The effects are powerful.”

Some neurodegenerative diseases may arise from too little ATP, said Julie St-Pierre, a co–first author of the paper and now a postdoctoral fellow at the Institute for Research in Immunology and Cancer at the University of Montreal. She suspects some of PGC-1 alpha’s benefits may come from increased ATP production as well, but those experiments have yet to be done.

The papers suggest a potentially broad role for PGC-1 alpha in ameliorating neurodegeneration, said Pere Puigserver, an assistant professor of cell biology at Johns Hopkins University School of Medicine, who first cloned PGC-1 alpha as a postdoc in Spiegelman’s lab eight years ago. As of November, he will move his lab to DFCI and become an assistant professor at HMS. “As it relates to health and disease in people, two important outcomes of future research will be evidence that mutations in PGC-1 alpha can predispose humans to disease and [discovery of] a way to increase PGC-1 alpha function in neurons to maintain survival,” he said.

—Carol Cruzan Morton

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