Demetrius (Jim) M. Maraganore, M.D.

Parkinson's is about communication. It is very complex, but in a way, it is also that simple. In an area of the brain called the substantia nigra, a specialized set of neurons sends signals in the form of a neurotransmitter called dopamine. The signals travel to the striatum via long fibers called axons. The activity of this pathway controls normal movements of the body.

When neurons in the substantia nigra degenerate, the resulting loss of dopamine causes the nerve cells of the striatum to fire excessively. This makes it impossible for people to control their movements, leading to the familiar and most obvious symptoms of Parkinson's. Visible symptoms are important here because diagnosis still depends on clinical observation. There are no blood or lab tests that can confirm Parkinson's disease.

Many Parkinson's patients eventually lose 80 percent or more of their dopamine-producing cells. While the cause of this neuronal death remains uncertain, researchers have identified several cellular characteristics that are common in this disease and which appear to play a role in the neurons' degeneration. Chief among these is the presence of Lewy bodies in neurons of the substantia nigra, the brainstem, and other parts of the brain. Lewy bodies are dense clumps of proteins.

Another cellular characteristic of Parkinson's is the presence of Lewy neurites — nerve fibers swollen with proteins. The one critical to our story is called alpha-synuclein. It may interfere with transmission of nerve signals or other important neuronal functions.

On the Edge of One Treatment

Mayo Research: A Triple Threat to Disease
Mayo Clinic conducts complementary research in Parkinson's disease across its three locations – Arizona , Florida and Minnesota . The combination of their respective strengths allows Mayo researchers to observe patients and define the biochemical basis of risk factors, create experimental models in the laboratory, develop therapies and then come back to the patient with a treatment – a very unique collaboration. Researchers in Jacksonville , Florida conduct basic neuroscience research in Parkinson's, while Mayo Clinic in Arizona is a leader in clinical trials for the disease. Discovery's Edge will feature more ongoing Parkinson's investigations by Mayo researchers in future issues.

In 1997, researchers at the National Institutes of Health uncovered the role of alpha-synuclein. Mayo Clinic researchers solidified this evidence. They studied an 80-year span of an Iowa family, discovering that Parkinson's in that family was caused by inheriting three copies of the alpha-synuclein gene from their affective parent. That meant that family members with Parkinson's had four copies of the gene instead of two and were making twice as much of this protein. The protein doesn't have to be abnormally formed or abnormally functioning to cause the disease; there just has to be too much of it. So, why not develop treatments to reduce alpha-synuclein? Such a treatment has been conceived at Mayo Clinic. A patent has been filed. The goal is to reduce the expression of this protein in patients with Parkinson's. The gene can be turned off without affecting normal health. Reducing the protein could halt progression.

Unfortunately, this is probably not the sole cause of Parkinson's. The mutation discovered is a rare cause, but every patient with Parkinson's disease has abnormal accumulations of this protein in Lewy bodies.

A Genomic Map in One Year

In 2004, NIH and The Michael J. Fox Foundation provided approximately $2.8 million in funding to create the first whole genome study, or genetic map, of Parkinson's disease - to be accomplished within one year. Mayo Clinic was chosen from 60 initial applications to be funded. This is a remarkable award of $2.8 million dollars for just one year. The award brought together Mayo Clinic's patient database and Perlegen Sciences, a company that created a high-density array genotyping technology.

"This represents one of the first large-scale whole genome association studies of any disease," said the study's first author, Mayo Clinic neurologist Demetrius Maraganore, M.D. of the Parkinson's Disease Lab, "It is something we've wanted to do for years, and now we finally had the technology and funding to make it happen."

Parkinson's and Alzheimers: More alike than not?
There are many, many different clues supporting a strong relationship between Parkinson's disease and Alzheimer's disease. Two Mayo scientists, Len Kerland and Don Mulder conducted a study in Guam in the 1950's on an epidemic of nerve degeneration on the Island , where there was an abnormal prevalence of ALS, Parkinson's disease and Alzheimer's disease, a strong indication that these disorders may share common underlying mechanisms. Of the 30,000 genes in a human, they only make so many proteins. Further, the Lewy body characteristic in Parkinson's disease is not entirely specific to Parkinson's. There are other Lewy body disorders. Much of the proteins that contribute to Parkinson's disease also contribute to Alzheimer's disease and vice versa. For example, alpha-synuclein was initially discovered as playing a role in modifying amyloidal protein, which is at the very heart of Alzheimer's disease (see DE article).
"What we learn from curing Parkinson's disease will allow us to cure Alzheimer's disease or multiple sclerosis or other brain disorders much earlier because it will set the stage for how to successfully discover the causes of the disease and how to successfully cure it," says Dr. Maraganore.

The combination of Mayo's extensive patient experience, Perlegen's state-of-the-art genotyping technology and significant funding, accelerated Parkinson's research by quickly providing a comprehensive source of information to scientists everywhere. These genomic findings also have high potential for translation: identifying new targets for drug therapies, or a biomarker, or diagnostic test.

The team met the aggressive timeframe, and in September 2005, published the first large-scale whole genome map of genetic variability associated with Parkinson's disease. Their results highlight changes in 12 genes that may increase the risk for Parkinson's in some people.

Significance and Key Findings

Nearly 200 million gentic tests (genotypes) were completed. The team looked at the DNA from 1,000 individuals: 500 sibling pairs—one of whom has Parkinson's disease and one of whom does not, by studying more than 200,000 single nucleotide polymorphisms (SNPs -- pronounced "snips"), unique genetic markers that are spread evenly across the human genome. The purpose was to determine those that vary most between the Parkinson's and non-Parkinson's samples. After identifying these markers, they were furthered analyzed in an additional population consisting of 300 people with Parkinson's and 300 unrelated people as controls.

In the first tier of the whole genome scan, researchers examined DNA from 443 case-sibling pairs; in the second tier, they genotyped 332 case-control pairs. That's a total of 775 pairs or 1,500 individuals total, with the goal of identifying all the major Parkinson's disease susceptibility genes as well as risk factor profiles associated with a high risk for the disease.

"To be most effective, a whole genome association study requires accurate testing of a large number of SNP markers that are distributed across the human genome in a dense and informative pattern. In this respect, our collaborators at Perlegen have set a new standard," said Dr. Maraganore.

The research also confirmed that variation in two previously known regions of the genome, PARK10 and PARK11, are likely associated with Parkinson's disease susceptibility. The study also identified ten additional SNPs that appear to be associated with Parkinson's susceptibility. Some are in or near genes with direct biological relevance to the disease.

Susceptibility genes are genes that may make some persons more or less likely to develop a disease, but do not directly cause the disease. In this study, the size of the effect was small for any single SNP; combinations of gene variants or interactions with environmental factors may be necessary to develop Parkinson's.

If confirmed, the finding of 12 potential susceptibility genes is significant. However, equally significant is that the study found no strong single genetic determinant of Parkinson's disease.