Revolutionizing the way we
treat Parkinson's

Stem cells, genetics and a guiding light fight
the degenerative disease

By Jennifer Laliberté

PD is a chronic, progressive disease characterized by the loss of dopamine-producing neurons, there's no definitive diagnostic tool, and there is no cure. But research is being conducted around the world to provide answers for the millions of people who are afflicted. Here's a roundup of some of the latest advances.

STEM CELL SAVIOURS?
Neurological diseases like Parkinson's are prime candidates for treatment by stem cell transplantation. Since embryonic stem cells have the potential to differentiate into any kind of cell in the body, they can, in theory, be used to replace the dopamine-producing neurons that are lost in PD. While studying the development of the central nervous system, Dr Thomas Perlmann and Dr Johan Ericson of the Karolinska Institutet in Sweden stumbled upon a crucial bit of information that may lead to a breakthrough: they figured out how a stem cell becomes a dopamine neuron in the first place.

The duo discovered that two genes are selectively expressed in dopamine progenitor cells — those that are midway between stem cells and bona fide dopamine-producing neurons — Lmx1a and Msx1. In a later experiment, they found that Lmx1 alone is sufficient and necessary for the development of dopamine neurons in the midbrain of chicks. "In the use of stem cells for therapy, it's of utmost importance to make the correct cell type," explained Dr Perlmann. "Our data establish Lmx1 and Msx1 as critical intrinsic dopamine-neuron determinants in vivo and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease." Their findings are reported in the January 27 issue of Cell.

Up to now, there have been few attempts at fetal brain tissue transplants in Parkinson's disease patients and the results have been mixed. And the use of fetal tissue is an ethical minefield. The therapeutic use of stem cells has proven contentious as well, but it's also an exciting source of hope for PD sufferers. "The use of cell replacement therapy in the treatment of Parkinson's disease is fraught with many problems," said Dr Perlmann. "However, clinical trials have provided important proof of the principle that transplantation of dopamine neurons might work in patients."

FOREVER IN GENES
Genetics is one of the most exciting and prolific areas of PD research. A greater understanding of the genetic component of the disease would have far-reaching repercussions; not only could such information help scientists unravel how PD works, but it could also be used to develop new animal models that accurately mimic the disease, identify potential new drug targets and improve diagnosis.

Several genes have been linked to PD, but the key is finding out exactly how they are involved in the disease. As research progresses, these mechanisms are becoming increasingly clear. For example, a gene called DJ-1 has recently been shown to act as a 'bodyguard' for dopamine neurons in the brain. If the cell is subjected to oxidative stress, DJ-1 protects it by turning on production of antioxidant proteins — it even gets down in the trenches to absorb some of the cellular damage itself. And if cellular garbage is accumulating in the cell, DJ-1 calls in reinforcements to clean up the mess. By shedding light on this important mechanism, researchers from the University of Colorado at Denver and Health Sciences Center's School of Medicine have shown us how a mutated DJ-1 makes dopamine-producing cells vulnerable. "If we can find drugs that increase activity of the DJ-1 gene, we may be able to stop the relentless progression of Parkinson's disease — even in patients who don't have mutations in the gene," said Dr Curt Freed, a co-author of the study. "Stopping the disease in its earliest stages would be a tremendous breakthrough." The study was published in the December 30 issue of the Journal of Biological Chemistry.

Of course, DJ-1 isn't the only genetic target under investigation. In the past year, mutations in LRRK2 have emerged as one of the most common genetic causes of PD, accounting for five to six% of familial cases. But because the protein is very large, it hasn't been analyzed in depth, and no one really knew what it did — until now. Researchers at Johns Hopkins' Institute for Cell Engineering have shown that the large protein is actually a kinase — a class of molecules that controls the activity of other proteins by attaching a group of phosphates onto them, a process known as phosphorylation. They also noted that two of the mutations — ones that have been linked to PD — increase LRKK2's phosphorylation abilities. "The next step is to prove that LRRK2 overactivity results in the death of brain cells that produce dopamine, the defining pathology of PD, and to figure out how it does so," noted co-author Dr Ted Dawson. These findings appeared in the November 15 issue of PNAS.

A STIMULATING INNOVATION
Deep brain stimulation — a surgical procedure where electrodes are implanted directly into the brain — was approved for the treatment of Parkinson's a few years ago, in cases where standard drug therapies don't, or no longer, work. The treatment has proven very effective, but it's very invasive. Now, a new guidance system that relies on computerized brain-mapping techniques has made it a much more appealing treatment for doctors and patients alike.

The structure where the electrodes have to be placed is not visible to the naked eye, so up until now, the surgeon was flying blind during this procedure which could drag on as long as 12 hours — and that's for a single electrode, most patients need two. "It's something like playing a big game of Battleship," said Dr Peter Konrad, co-developer of the new system. "You don't know where the target is until you've made a hit." The procedure is also extremely rough on patients, who have to stay awake throughout, locked to the bed to keep them immobile. But now, a team of electrical engineers and neuroscientists at Vanderbilt University has eliminated the guesswork by developing an autopilot system that guides the surgeon to the right spot. The system predicts the location of the target area by combining data from the patient's own MRI to a built-in brain atlas. By pointing the surgeon in the right direction, this advance has reduced the length of the procedure from two days to five hours.