October 26, 2009 (Honolulu, Hawaii) — A mutant enzyme that causes Gaucher's disease has been shown to function as a substrate of an enzyme produced by the parkin gene. Parkin gene mutations are the most common cause of early-onset Parkinson's disease, whereas Gaucher's disease results from mutations in the gene encoding lysosomal glucocerebrosidase.
The new findings explain the increased risk for Parkinson's disease observed in Gaucher's disease patients — as much as 5 times that of the general population. The results were presented here at the American Society of Human Genetics 59th Annual Meeting.
Gaucher's disease is a rare autosomal recessive lysosomal storage disorder that occurs in approximately 1 in 40,000 to 60,000 people worldwide. However, its incidence among Ashkenazi Jews might be as high as 1 in 450. Patients with 2 mutant copies of the glucocerebrosidase gene (GBA) lack the normal lysosomal enzyme and are unable to metabolize glucocerebroside, a fatty substance that builds up in the cells. Cellular damage can be evident in the lungs, liver, bone marrow, spleen, and brain.
Parkinson's disease occurs in approximately 2 in every 1000 people in the United States. Its incidence rapidly increases with age, affecting about 1% to 2% of people older than 60 years; only 4% of cases are found in people younger than 50 years. The risk of developing Parkinson's disease depends on both genetic and environmental factors. The normal parkin gene encodes an E3 ubiquitin-protein ligase that functions in endoplasmic reticulum-associated degradation. In patients with mutations and decreased function of parkin, its usual substrates accumulate and damage dopaminergic neurons, leading to the tremors and stiffness characteristic of Parkinson's disease.
Mia Horowitz, PhD, from the Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University in Ramat Aviv, Israel, described the research that tested the possibility that parkin might function as an E3 ligase of mutant glucocerebrosidase variants. The study examined the interactions between parkin and mutant glucocerebrosidase.
Cells transfected with a parkin-expressing gene exhibited no change in the stability of normal glucocerebrosidase; however, the stability of mutant glucocerebrosidase decreased. Similarly, normal parkin significantly affected ubiquitination — a process in which proteins are tagged for transport to the proteasome for degradation — and the subsequent degradation of mutant glucocerebrosidase molecules.
"We think that the parkin, which is present in dopaminergic cells, . . . is responsible for degradation of substrate in the cells of the substantia nigra," Dr. Horowitz told Medscape Pathology. "When there is mutant glucocerebrosidase in the cells, [parkin] gets occupied with mutant glucocerebrosidase and fails to take care of its natural substrate. This is known to lead to Parkinson's disease," explained Dr. Horowitz.
Other recent studies have demonstrated that carriers of the GBA mutation, previously thought to be unaffected by their heterozygous state, are also at greater risk of developing Parkinson's disease. Jerry Vockley, MD, PhD, professor of pediatrics at the University of Pittsburgh School of Medicine, professor of human genetics at the Graduate School of Public Health, and chief of medical genetics at the Children's Hospital of Pittsburgh of UPMC in Pennsylvania, was comoderator of the session in which Dr. Horowitz presented. He talked with Medscape Pathology about the clinical implications of the new findings.
"The issue here is that the heterozygote state for any disorder is much more common than the homozygote state. Especially in a subpopulation like the Ashkenazi Jewish, where the carrier status for Gaucher's disease is so common [as high as 1 in 15], it really alerts us now that we have to worry about . . . the risk for development of Parkinson's [disease] in that specific subgroup," said Dr. Vockley.
Dr. Vockley emphasized that genetics has passed the point of looking at the single function of a gene or the immediately characterized biochemical abnormality that occurs with a single-gene enzyme defect. Instead, geneticists need to understand more about interactions at the cellular level.
"Here, clearly, are abnormalities in the gene for an enzyme that cause problems that are completely unrelated to the basic biochemical function of the gene," he said. "Some of the functional abnormalities that we're seeing may not be related as much to the primary enzymatic function as to its role in holding a multifunctional complex together. . . . This is becoming a recurrent theme and may be an increasingly important one as we move forward," Dr. Vockley noted.
Dr. Horowitz and Dr. Vockley have disclosed no relevant financial relationships.
American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 60. Presented October 22, 2009.
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Cite this: Israeli Study Finds Molecular Link Between Parkinson's Disease and Gaucher's Disease - Medscape - Oct 26, 2009.