WSJournal. Mad-Cow Disease May Hold Clues To Other

WSJournal. Mad-Cow Disease May Hold Clues To Other Neurological Disorders
http://online.wsj.com/article/SB1000142412788...ljournal_0

Scientists believe new ways to treat Alzheimer's, Parkinson's and Lou Gehrig's disease could emerge from research into another neurodegenerative disorder: mad-cow disease.
More About Alzheimer's

Is Early Detection Useful If a Disease Has No Cure?
Alzheimer's Families Clamor for Drug
Gene Points to Role of Inflammation in Alzheimer's

The rare bovine disorder, which infects cattle, and the human form, called Variant Creutzfeldt-Jakob disease, both fall into a category of so-called prion diseases, caused by aberrant proteins that spread aggressively from cell to cell.

While the human variant of mad-cow disease isn't normally lumped together with Alzheimer's, Parkinson's or Lou Gehrig's disease, which affect millions of mostly older people world-wide, the conditions share the ability to spread and wreak havoc through the body. And although there isn't evidence that these more common neurological disorders are transmissible to people, researchers are finding that each condition is associated with a similar deformation in the structure of particular proteins needed for normal healthy functioning.

Dozens of diseases are believed to be linked to deformed proteins, including Type 2 diabetes, cataracts and a type of emphysema. What sets prion diseases apart is the ability of their aberrant proteins to induce healthy ones in other cells to also become deformed, leading to brain damage and dementia. In laboratory work with mice, evidence is emerging that Alzheimer's and other major neurodegenerative conditions may follow a similar pattern.
When Proteins Go Bad

Some scientists believe neurodegenerative disorders like Alzheimer's and Parkinson's may be driven by certain deformed proteins that cause the disease to spread. The phenomenon known as 'misfolding,' which causes those proteins to be malformed, plays a role in a range of diseases. Some examples:

Type 2 diabetes: People with the disease have deformed proteins in their pancreas, which can impact insulin production.
Atherosclerosis: Protein misfolding may cause forms of cholesterol to build up in blood-vessel walls.
Cataracts: People with the disease have aberrant proteins that accumulate in the eye lens
Cystic fibrosis: Improper folding of the CRTR protein plays an important role in this genetic condition.
Emphysema: Misfolded proteins build up in the liver and don't reach the lungs, driving one type of this disease.

Source: The Journal of Biological Chemistry, Biochemica et Biophysica Acta and others.

Deformed proteins can't be mended, but stopping cell-to-cell spread provides a new therapeutic target. "Arrest it and we can potentially stop the disease," says Neil R. Cashman, a neurologist in the Brain Research Centre at University of British Columbia, who conducts research on amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease. Dr. Cashman also works as chief scientific officer of a biotech company developing possible ALS therapies based on this method.

Proteins, after being formed in the body, take on a three-dimensional shape in a process called folding. Each protein has a distinctive folded shape that is essential for it to carry out its functions, such as regulating body processes and warding off infection. Failure to fold into the correct shape produces inactive proteins that are often toxic. Cells have mechanisms to get rid of misfolded proteins, but aging and other factors can slow or harm this process. In so-called prion diseases, the toxic proteins spread from cell to cell and induce healthy proteins to misfold.

In one experiment, researchers at the University of Pennsylvania, in Philadelphia, injected a synthetic version of the toxic protein associated with Parkinson's disease into the brains of healthy mice. In a paper published in Science in November, they showed how the toxic protein spread from cell to cell in a prion-like fashion, resulting in the death of crucial dopamine-making neurons in the animals. The mice exhibited symptoms similar to those in humans with Parkinson's disease, including impaired motor coordination and balance.

Virginia Lee, who led the research team and is director of the Center for Neurodegenerative Disease Research at Penn, says they are now testing an antibody therapy that would stop the toxic misfolded proteins from spreading in the mice. If it works, it could provide a possible therapy to test in people with Parkinson's disease.

This fall, Todd Sherer, chief executive of the Michael J. Fox Foundation for Parkinson's Research, gathered scientists researching protein misfolding in a number of neurodegenerative conditions to explore ways to stop aberrant proteins from spreading. He says the latest papers led the foundation to "increase its support for this theory" in Parkinson's disease. The foundation is helping to fund a trial of a vaccine developed by Austrian biotech Affiris AG aimed at getting the immune system to produce antibodies that bind to and clear the toxic alpha-synuclein protein. The foundation is also considering funding other projects to stop cell-to-cell spread.

In the Alzheimer's arena, Kurt Giles, associate professor in the Institute for Neurodegenerative Diseases at the University of California, San Francisco, was one of the authors of a paper this year in the Proceedings of the National Academy of Sciences, showing that the amyloid-beta protein associated with Alzheimer's shares prion-like characteristics. The research team included Stanley Prusiner, the institute's director whose discovery of prions earned a 1997 Nobel Prize.

In their experiment, researchers injected amyloid-beta protein into one side of the mice's brains. They were then able to follow the disease's progression using a light-generating molecule that lighted up the mice's brains as the protein accumulated. The toxic protein set off a cascade of misfolding throughout the entire brain, just as it does in Alzheimer's.

"Amyloid-beta-protein misfolding triggered the spread of the disease from cell to cell," Dr. Giles says.

Such discoveries might have an impact in cardiac disease too, says Avijit Chakrabartty, professor in the department of medical biophysics and department of biochemistry at the University of Toronto. His lab has been looking at a type of cardiac disease called amyloid cardiomyopathy that is caused by misfolding of a particular protein. Clot busters and other heart-disease drugs typically don't work in these patients because it is the misfolded protein clogging their arteries, not cholesterol, he says.

There is an existing drug to treat a version of the disease that tends to run in families. But it currently isn't possible to distinguish cases that don't involve a genetic mutation, he says. Dr. Chakrabartty says his group is trying to develop a way to test for the misfolded protein in the blood and, once those patients are identified, treat them.

Write to Amy Dockser Marcus at amy.marcus@wsj.com