For release: Wednesday, December 19, 2001
Recent studies provide strong evidence that genetic factors influence susceptibility to the common, late-onset form of Parkinson's disease (PD). The findings improve scientists' understanding of how PD develops and may lead to new treatments or even ways of preventing the disease.
Until 1996, few people believed there was a genetic component to PD. The prevailing evidence suggested that environmental factors were largely or entirely to blame. Since then, studies have identified a clear genetic basis for two forms of PD that affect people younger than 50: one that affects a few families from Europe and another called autosomal recessive juvenile parkinsonism (ARJP) that affects some families in Japan. The first disorder is linked to a mutation in the gene for a protein called alpha-synuclein , and the second is linked to mutations in the gene for a protein called parkin . However, the role of genetics in the common, late-onset form of PD has remained controversial. In fact, several studies of twins have suggested that genes do not influence this form of PD. The new studies challenge that earlier work and suggest that multiple genes play a role in susceptibility to the disease.
One of the recent studies, 1 led by Margaret A. Pericak-Vance, Ph.D., of the Center for Human Genetics at Duke University Medical Center in Durham, North Carolina, and funded by the National Institute of Neurological Disorders and Stroke (NINDS), looked for a relationship between specific genetic markers and PD in 870 people from 174 families in which more than one person had been diagnosed with the disorder. They found evidence that five distinct regions, on chromosomes 5, 6, 8, 9, and 17, were associated with susceptibility to PD. The chromosome 6 region contains the parkin gene, which was previously associated only with early-onset PD. The familial link to chromosome 9 was found primarily in patients who do not respond to levodopa (a common treatment for PD) and the marker is located near a gene that is altered in another disorder called idiopathic torsion dystonia. This suggests that there may be a relationship between PD and dystonia. The strongest genetic association in families with late-onset PD was on chromosome 17, near the gene for a protein called tau . Tau is a component of neurofibrillary tangles, a specific brain abnormality found in other neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia with parkinsonism (FTDP), and progressive supranuclear palsy (PSP). Because people with PD do not have neurofibrillary tangles, researchers did not previously suspect tau as a factor in the disease. However, tau is important to normal cell function and it is possible that even minor abnormalities in how it works may lead to cell death, the researchers say.
A second NINDS-funded study, 2 led by Jeffrey M. Vance of Duke University, looked at specific variations within the tau gene and found evidence that three of the variations were linked to increased susceptibility for late-onset PD. A third study, 3 conducted by scientists at deCODE genetics, Inc., of Reykjavik, Iceland, looked at 51 Icelandic families with late-onset PD and linked the disease in these families to a region on chromosome 1.
Previous studies have suggested that other genes, including ubiquitin carboxy-terminal hydrolase (UCH-L1) and genes on chromosomes X, 1, 2, and 4, influence susceptibility to PD in some families. It also is possible that additional, still-unidentified genes may play a role in specific populations, the researchers say.
Knowledge of the genes that influence PD is potentially useful in a number of ways. For example, testing people for specific genes may help to identify subtypes of PD and lead to a better understanding of how to treat different groups of patients. "We could be talking about Parkinson's diseases—not just one disease," says William K. Scott, Ph.D., of Duke. Certain drugs and other treatments may be more or less effective in people with specific subtypes of PD.
The researchers stress that the genes linked to the late-onset form of PD are susceptibility genes—they do not cause the disorder all by themselves. Environmental factors probably interact with these genetic variations in ways that cause the disorder in some people.
While it is still unclear how the different genes may interact with the environment to cause PD, each identified factor represents an important piece in the puzzle, the researchers say. Parkinson's is a complex disease, and each genetic factor could have many effects and interactions with other genes that may influence the development and symptoms of the disorder. "We've got the outside of the puzzle—now we need to fill in the middle," says Dr. Pericak-Vance. Researchers think the various genes and environmental factors that influence PD may all affect a single pathway, or series of biochemical interactions, that leads to the disease. Understanding the steps of the pathway should help researchers develop strategies to interrupt the process and lead to new treatments or even ways to prevent the devastating disease.
References:1 Scott WK, Nance MA, Watts RL, et. al. "Complete genomic screen in Parkinson disease: evidence for multiple genes." Journal of the American Medical Association 2001 Nov 14;286(18):2239-44.
2 Martin ER, Scott WK, Nance MA, et. al. "Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease." Journal of the American Medical Association 2001 Nov 14;286(18):2245-50.
3 Hicks A, Petursson H, Jonsson T, et. al. "A susceptibility gene for late-onset idiopathic Parkinson's disease successfully mapped." American Journal of Human Genetics Oct 2001, 69, Abstract 123:200 (Supplement).
- By Natalie Frazin
Last Modified May 6, 2013