The nerve cell death that helps drive Parkinson's disease may be triggered by a harmful modification in a particular nerve cell protein, new research reveals.

The modification in question -- an apparently toxic mix of the protein alpha-synuclein and the critical neurotransmitter dopamine -- can be found in all Parkinson's patients, researchers say.

The change short-circuits a process that allows aging nerve cells to stay healthy by purging themselves of damaged molecules, researchers explain in the Jan. 2 online issue of The Journal of Clinical Investigation.

"The general idea is that, in Parkinson's, the neurons accumulate lots of garbage," explained study author Dr. Ana Maria Cuervo, an associate professor in the department of anatomy and structural biology at Yeshiva University's Albert Einstein College of Medicine, in New York City.

"Normally," she said, "this garbage is removed before it builds up, and is dumped into garbage containers called lysosomes, which make sure things can move about the neurons fast and freely."

Such a filtering process for disposing of damaged molecules is known as "autophagy," a term that literally means "self-eating."

"But sometimes, this mechanism fails," Cuervo noted. "And now we have found the reason why. It is because of the formation of this particular modified protein, which acts kind of like chewing gum in the middle of the nerve cell."

"It's not a normal protein," she stressed. "It's very sticky, and any other proteins passing by get stuck to it, so you get all these abnormal things, these stones in the middle of the cell's highways, that are not being removed, and eventually the [brain] cells can't move things around as they should, and they die."

In an earlier effort, the same research team had found that mutant forms of alpha-synuclein -- as opposed to modified forms -- also block the desired breakdown of damaged nerve cell molecules. Such mutant proteins are present in the 5 percent to 10 percent of Parkinson's patients struck with a relatively rare, familial form of the disease.

"But the novelty of our work today is that the modified protein mechanism we found this time will apply to all Parkinson's patients," noted Cuervo. "And so it becomes possible that in the future we can design drugs to improve the function of the garbage containers, the lysosomes, in all Parkinson's patients, and maybe overcome the problem that these nerve cells have handling the modified molecules."

Cuervo and her Einstein colleagues conducted the study, based on laboratory work with male rats, in collaboration with scientists from Columbia University in New York City, the University of Pennsylvania, and Harvard Medical School in Boston.

The National Parkinson Foundation estimates that 1.5 million Americans are affected with Parkinson's disease, the most common degenerative brain disorder affecting movement.

The nerve damage that's characteristic of this incurable disease brings about a dramatic loss of muscle control, typically manifesting as tremors, stiffness, and a loss of balance and agility.

Though optimistic about her work, Cuervo emphasized that translating the latest findings into new preventive and curative interventions will require a lot more research and time.

"I want to be very cautious," she said. "We are far from a final cure. It's not something we can do tomorrow. It's going to take some time. But now we know what the problem is. And we think that we have something, a target, to focus on."

Nonetheless, Dr. Robert Burke, director of the Morris K. Udall Parkinson's Disease Research Center of Excellence at Columbia University, called the new findings a "big step forward."

"Their first finding was only related to the mutant form of the protein which is very rare," he noted. "Whereas here they have shown that dopamine-modified neurons also block the system. This means they now have something that appears applicable to patients with the much more common sporadic form of Parkinson's. And that is very, very helpful."

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged.

Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death.

These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle"that may be considered the underlying cause of neurodegenerative pathogenesis.

Author: Kristen MalkusElpida TsikaHarry Ischiropoulos
Credits/Source: Molecular Neurodegeneration 2009, 4:24