University of Minnesota
May 4, 2012
Micrograph of brain stem from a transgenic mouse producing large amounts of alpha-synuclein. Central feature is the stained cell body of a neuron. Blue: cell nucleus. Red: alpha-synuclein molecules. Green: "chaperone" protein that tries to fix misfolded proteins. Yellow: area where alpha-synuclein and the chaperone co-localize. Its size indicates the chaperone is overmatched and the cell is self-destructing. Photo: Emanuela Colla
A wayward protein may be key to understanding the disease
By Deane Morrison
When actor Michael J. Fox was diagnosed with Parkinson's disease in 1991, he became one of some 2.5 million Americans afflicted with it or a related disease every year.
The $50 billion spent annually on Parkinson's and a sister disease is second only to the $172 billion spent on Alzheimer's disease.
No wonder University of Minnesota neuroscientist Michael K. Lee is excited about finding what may be the key to how Parkinson's disease kills neurons. He and his colleagues have discovered that a protein normally present in brain tissue can form clumps inside neurons, which may poison the cells.
They also found that at least one drug can relieve both the protein clumping and the symptoms in animal models of Parkinson's disease. The work was published in March in the Journal of Neuroscience.
"Our approach—targeting the underlying pathology of Parkinson's disease—will help make existing treatments more effective because they require relatively intact neurons," says Lee, who is co-director of the U's Center for Neurodegenerative Diseases, a part of the Institute for Translational Neuroscience. "Our work should lead to ways to slow degeneration, meaning more intact neurons."
Normal proteins, abnormal behavior
Parkinson's disease is similar to Alzheimer's disease and ALS (Lou Gehrig's disease) in that it involves abnormal behavior by what biochemists call housekeeping proteins—unobtrusive proteins whose functions aren't necessarily known or noticed. The protein Lee studies, called alpha-synuclein, is normally found in neurons but performs an unknown function. It inhabits the area outside the nucleus, where, among other things, proteins are synthesized in assembly-line fashion on membranes of a complex called the endoplasmic reticulum (ER).
Before they leave the ER, the newly synthesized proteins must be folded into the proper shape for carrying out their functions. Unfolded or misfolded proteins are useless, if not toxic, and are routinely destroyed.
A schematic protein before and after folding. Some parts of the folded protein have arranged themselves into sheetlike or coiled conformations necessary for it to perform its function. Image: Wikipedia
But as animals age, molecules of the alpha-synuclein protein may start folding the wrong way and aggregating into small clumps called oligomers. Oligomers of alpha-synuclein are toxic and can stick together to form even larger clumps that cause ER to break down. Until Lee and his team found them associated with the ER, alpha-synuclein oligomers had only been seen in test tubes and had not been observed in Parkinson's disease.
"We saw them in mice [neurons] and in post-mortem human brains," says Lee. "Brains with Parkinson's disease had a much higher level than [those that didn't]."
Lee and his colleagues suspected that accumulating alpha-synuclein oligomers caused a condition called ER stress, which may be triggered by the presence of unfolded or misfolded protein in the ER. When that happens, sensors within the ER called chaperones swing into action. The chaperones attach themselves to the miscreant proteins and help them either refold or get destroyed.
"But if that response is inadequate, the cell activates a self-destruct mechanism that leads to cell death," says Lee.
Is ER stress caused by accumulating alpha-synuclein oligomers an important factor leading to death of neurons in Parkinson's disease?
To find out, Lee and his colleagues turned to Salubrinal, an experimental compound known to protect against chronic ER stress. With researchers at Johns Hopkins University, they found the drug significantly delayed the onset of symptoms in mouse models of Parkinson's disease. With Swiss researchers, they also used a rat model where the dopamine-secreting neurons—the type most affected in Parkinson's—were induced to churn out toxic alpha-synuclein. The drug improved both the rats' limb movement and the neurons' health.
Lee hopes to test another compound that relieves ER stress and is already used to treat hypertension. While this isn't expected to cure Parkinson's disease, any drug that delays the onset or reduces the severity of symptoms would reap large savings in dollars and emotional stress. But Lee knows he must be patient.
"There are many people pushing treatments prematurely," he says. "We want to have real confidence before bringing a treatment forward."
Published in 2012