"Tau is the first example of a gene thought to be involved in susceptibility leading to late-onset Parkinson's disease. Tau by itself does not cause Parkinson's, but we found that a form of the tau protein may make some people susceptible to Parkinson's disease," said Dr. Jeffery M. Vance, senior author of the study and director of the Genomics Research Laboratories at Duke's Center for Human Genetics.
In a companion paper published in the same issue of JAMA, Duke researchers suggest that multiple genes are involved in the etiology of late-onset Parkinson's. The findings provide strong evidence of a genetic component to Parkinson's disease, a disorder of the nervous system that causes tremors and muscular rigidity, affecting more than 1 million people in the U.S. Both Duke studies were funded by grants from the National Institutes of Health and by GlaxoSmithKline.
Tau is a protein important in maintaining the structure of brain cells. When tau proteins malfunction, as in the case of Alzheimer's patients, they bunch together in neurofibrillary plaques and tangles, leaving fibrous deposits in the brain. Tau protein formation is related to the severity of disease; the more advanced the stage of disease, the more tau deposits in the brain.
Unlike with Alzheimer's disease, tau deposits have not been observed in the brains of autopsied patients with late-onset Parkinson's, a fact that led many scientists to abandon the theory that the tau gene might be directly involved. The Duke researchers noted, however, that mutations in the tau gene have been known to cause frontotemporal dementia with Parkinson's disease, a rare degenerative disease often referred to as FTDP17 because of a mutation found on Chromosome 17. FTDP17 is associated with behavior problems, memory loss and movement disorders. They also noted that the tau gene has been strongly associated with a second form of a Parkinson-like disease: progressive supranuclear palsy (PSP), a rare neurological disease that affects motor skills such as coordination, balance, vision and speech.
For these reasons, the researchers chose to take a fresh look at the tau gene's possible role in causing Parkinson's. They looked for variations in single nucleotide polymorphisms (SNPs), the differences among individual human beings in specific letters of their genetic code. The researchers studied whether differences in five of these letters might be involved. After reviewing blood samples from 1,056 individuals in 235 affected families, they found significant evidence of linkage between the tau gene and late-onset Parkinson's in three of the five variable letters, or SNPs.
The cause of Parkinson's disease is unknown, but it is thought to have both genetic and environmental factors. While most scientists agree there is a genetic link, the consensus has been that genetics is important mostly in the rare, early-onset form of the disease, usually diagnosed before age 50. Two genes (a-synuclein and parkin) have been identified that lead to the rare, early-onset form of Parkinson's disease. The Duke study did not focus on mutations in the tau gene. Instead, researchers focused on identifying these normal SNP variations, which are small differences between individuals that occur in proteins but generally don't change a protein's overall function. However, some forms or polymorphisms may make the person more susceptible to a specific medical problem, as with light pigmented skin and sunburn. Despite evidence that hinted at the possibility of a direct link from the tau gene to late-onset Parkinson's, scientists questioned whether such a direct link existed.
"There is no known abnormal tau pathology in Parkinson's disease, like there is in PSP and FTDP-17. But a susceptibility gene does not have to be mutated to the point that it is nonfunctional to be significant. We showed that with APOE4," Vance said. APOE4 - or apolipoprotein-E4 - is a protein identified in 1993 by Duke researchers who found that the failure of an inherited form of APOE4 can lead to Alzheimer's disease.
"Currently we have a form of tau that is associated with Parkinson's disease. Now, the question is, 'What form of tau causes increased susceptibility to Parkinson's?' Because the tau gene is a large gene with 16 protein-coding sequences, significant work will be needed to identify these specific polymorphisms. "It's still possible that despite the strong evidence for association within the tau gene, another gene nearby might be the true susceptibility gene. Yet, the evidence of linkage in the region and biological function point strongly to tau as a susceptibility gene for common Parkinson's disease," Vance said. The Center for Human Genetics is one of five research centers within Duke's Institute for Genome Sciences and Policy (IGSP). The IGSP, established in 2000 with $200 million in institutional funds, represents Duke University's comprehensive response to the broad challenges of the genomic revolution. The other four research centers include: the Center for Genome Technology, the Center for Human Disease Models, the Center for Bioinformatics and Computational Biology and the Center for Genome Ethics, Law and Policy.
The Duke research team members include: Eden R. Martin, William K. Scott, Jeffrey M. Stajich, Robert C. Ribble, Michael W. Booze, Allison Rogala, Michael A. Hauser, Fengyu Zhang, Burton L. Scott and Margaret A. Pericak-Vance. Other researchers included: Martha A. Nance, Struthers Parkinson Center, Golden Valley, Minn.; Ray L. Watts, Emory University School of Medicine, Atlanta, Ga.; Jean P. Hubble, Ohio State University; William C. Koller and Kelly Lyons, University of Miami School of Medicine; Rajesh Pahwa, University of Kansas Medical Center; Matthew B. Stern and Amy Colcher, University of Pennsylvania Health System; Bradley C. Hiner, Marshfield Clinic, Marshfield, Wis.; Joseph Jankovic and William G. Ondo, Baylor College of Medicine, Houston; Fred H. Allen Jr., Carolina Neurologic Clinic, Charlotte, N.C.; Christopher G. Goetz, Rush-Presbyterian-St. Luke's Hospital, Chicago; Gary W. Small and Donna Masterman, University of California; Frank Mastaglia and Nigel G. Laing, University of Western Australia; Rachel A. Gibson, Lefkos T. Middleton and Allen D. Roses, GlaxoSmithKline; and Jonathan L. Haines, Vanderbilt University Medical Center.