Mayo discovery could cure Parkinson's, Lou Gehrig's

Scientists have discovered the defect that damages the brain's neurons

By Jeremy Cox

Story updated at 5:37 AM on Monday, Jan. 12, 2009

Of the billions of people who have ever walked this planet, only about 100 have been diagnosed with Perry syndrome.

So why would an international team of scientists led by a Mayo Clinic Jacksonville researcher spend seven mostly frustrating years looking into obscure corners of the human genome in search of its cause?

For the chance to unlock a key biological doorway that could lead to better treatments - or even a cure - for Parkinson's disease, Lou Gehrig's disease and depression.

In May, the team discovered what it was looking for, complete with a eureka moment. The findings appear today in the online edition of Nature Genetics and in the journal's February issue.

"To me, it's one piece in the puzzle of the whole picture of neurodegeneration," said Matt Farrer, the study's lead author and a Mayo Jacksonville neuroscientist.

The team's hunt uncovered among Perry syndrome patients a genetic defect in the protein that serves as the molecular motor for all of the body's cells. For reasons still unknown, the defect only affects neurons, or brain cells, in the midbrain, the part that controls muscle movement.

Perry syndrome was first recognized in 1975 as a distinct illness. Its symptoms are so similar to Parkinson's disease that doctors didn't realize for decades that something else was to blame for their patients' deterioration, Farrer said.

A person with the Perry defect typically sees the first signs around 50 years old. The syndrome begins with the onset of depression so devastating that one-third of patients commit suicide.

Those who survive the first stage, though, face a grim decline: Parkinson's-like symptoms and weight loss, followed by difficulty breathing and loss of bowel control. Most patients die within two to 10 years.

Farrer and the other researchers analyzed blood samples taken from four Perry syndrome-prone families. In all, the study included 40 people from Canada, France, Japan and the United States.

What followed were months of eye-blurring analysis in which researchers worked their way down the entire universe of genetic possibilities to the basic building blocks of DNA - nucleotides.

Just one variation out of billions - that's what Jenny Kachergus was looking for that day in May when a colleague in the Mayo lab called her over to look at a computer screen.

All the research analyst needed to see was one out-of-place line on a graph jammed with lines to know what she was looking at.

"Our jaws just dropped to the floor," Kachergus recalled last week.

The line showed a mutation in a group of proteins called dynactin, the cell motor. As far as Farrer can tell, the genetic defect causes neurons to go haywire and eventually die.

Erika Holzbauer, a University of Pennsylvania scientist who wasn't involved in Farrer's study, called the finding "exciting."

"That hopefully will give us clues as to why these cells are uniquely vulnerable to loss of function of that protein," she said. "If we have a clue of what's going wrong, we have the key to fixing what's wrong."

The next step is learning exactly what happens in the dying brain cells, said Holzbauer, who plans to work with Farrer on a component of that effort.

Farrer's team included researchers from Canada, France, Japan and Turkey. Their work was backed by the Pacific Alzheimer Research Foundation of British Columbia and the National Institutes of Health.

jeremy.cox@jacksonville.com, (904) 359-4083