SAN FRANCISCO—Overproduction of the normal form of the alpha-synuclein gene may cause Parkinson’s disease in a single family, a finding that increases the understanding of how synucleinopathies lead to disease and may lead to new therapeutic strategies. This research, based on a rare familial form of early-onset Parkinson’s disease, is further evidence that a given genetic cause can lead to multiple clinical and pathologic synucleinopathies in one family, said Katrina Gwinn-Hardy, MD.

“We know that alpha-synuclein is involved in multiple system atrophy,” said Dr. Gwinn-Hardy. “We know that alpha-synuclein is causal for Parkinson’s disease. We’ve also seen alpha-synuclein to be important to diffuse Lewy body disease. This clinical and pathologic range has been shown in this particular single family [the Iowa kindred], and it’s due to four, instead of two, copies of normal alpha-synuclein. They make twice as much alpha-synuclein as they should, and it deposits in neurons and kills them. I suspect that other causes of Parkinson’s disease, including sporadic causes, may involve overproduction of alpha-synuclein or failure to effectively break down alpha-synuclein.”

Dr. Gwinn-Hardy is Program Director of the Extramural Research Program at the NIH/National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. She presented her team’s findings at the 128th Annual Meeting of the American Neurological Association.

“The fact that there are three copies of the normal gene where there should be one indicates that the normal gene product, protein, can cause disease if there is enough of it,” Dr. Gwinn-Hardy said. “We knew that mutations in this gene—alpha-synuclein—caused Parkinson’s disease. Therefore, we knew that abnormal protein caused disease. Now we know that the normal protein also causes disease if there is too much of it.”

Dr. Gwinn-Hardy said that the discovery is important for a couple of reasons. First, she explained, is that because most laboratories sequence for mutations, duplications or triplications might be missed in this and in other genes. “Future research will show whether this sort of cause is common in familial cases, or isolated,” she noted. “More importantly, however, is that it gives us new therapeutic targets; that is, because we have learned from this that an excess of normal alpha-synuclein causes disease, therapeutic targets that decrease the quantity or enhance the breakdown of this protein may be effective, in general, for Parkinson’s disease patients.”

TOO MUCH OF A GOOD THING?

Researchers have been studying the Iowa kindred for more than 70 years, and Dr. Gwinn-Hardy has been conducting research in the family for nearly the past decade. These family members have an autosomal dominant form of parkinsonism, she said. Clinically, they usually develop symptoms around age 45. However, the youngest age of onset has been about 24, while the oldest age of onset has been about 49. The form of Parkinson’s disease in this family is similar to typical Parkinson’s disease except for its early onset and very fulminant course, Dr. Gwinn-Hardy noted. The family has had a larger than expected number of people with Parkinson’s disease and related disorders compared with the general population. In addition, said Dr. Gwinn-Hardy, “The disease [in the Iowa kindred] follows well-delineated inheritance patterns—autosomal dominant—that lend themselves to gene discovery. We continue to study other large and smaller families toward other gene discovery as well.”

ON FURTHER ANALYSIS

Initially, genetic analyses of some family members showed no mutations in the alpha-synuclein gene. Therefore, the investigators had thought that a different genetic mutation in a region that cosegregated with disease, also on chromosome 4, may account for Parkinson’s disease in the family and had termed this other gene PARK4. “There was a peak on chromosome 4 at the alpha-synuclein gene, but when we sequenced that gene, it was normal,” said Dr. Gwinn-Hardy. “Therefore, we didn’t think that this was the cause of Parkinson’s disease in this family. However, another patient became ill, and we thought there must be a problem here.” It was this other peak, on the same chromosome, that was thought to contain the responsible gene, until this discovery.

As was further detailed in the October 31 issue of Science, Dr. Gwinn-Hardy and colleagues, including Andrew Singleton, PhD, of the National Institute on Aging, performed additional analyses of the entire genome. They found that one particular patient had four copies of the normal alpha-synuclein gene in the chromosome 4 pair where she should have had two. Because it was the normal gene, sequencing had always been normal. This multiplication of the alpha-synuclein gene—an abnormal triplication of three genes on one chromosome 4 and the normal one copy on the other chromosome 4—resulted in the patient having too much alpha-synuclein. It is believed that this protein buildup causes Parkinson’s disease symptoms.

“It’s not just the alpha-synuclein gene that’s triplicated here,” Dr. Gwinn-Hardy pointed out. “There are other genes there also, about 15 other genes, some with known functions. We haven’t found any relationship to abnormalities in those particular genes that might give us clues in terms of other phenotypic qualities, but of course we’re thinking about that.”

CHANGING COURSES AND OPINIONS

“Over the course of time, I think our thoughts regarding Parkinson’s disease have changed maybe even more than the disease manifestations in this family, and they’ve been diagnosed with a lot of different things by a lot of different clinicians,” said Dr. Gwinn-Hardy. “While I think the disease clinically varies within the family, I also think that we as neurologists have changed a lot too and probably will continue to change in terms of the way we think about these diseases.”

As to whether this finding is more ammunition for those who espouse genetic causes of Parkinson’s disease over environmental ones, Dr. Gwinn-Hardy replied, “I think that this shows that a single gene can cause the disease in a given family. However, this was already known from the work of others. It doesn’t address environmental causes per se. However, there are variables in the disease within this family. Some had onset as young as 19 years of age, others as late as 51, for example. Is this influenced by environmental or genetic causes? We continue to study this.”

Dr. Gwinn-Hardy’s work was conducted in collaboration with researchers from other institutions, including the Mayo Clinic, the National Human Genome Research Institute, the National Institute on Aging, and Georgetown University Medical Center. In addition to providing new clues by which Parkinson’s disease develops, the investigators believe that their findings also suggest another way of looking at the consequences of abnormal protein deposition in a variety of neurologic diseases, including Alzheimer’s disease. They also suggested that the mechanism of disease observed in their research is similar to that seen in people with Down syndrome, in which patients produce an excess of ß-amyloid, which accumulates and can lead to a form of Alzheimer’s disease.

Dr. Gwinn-Hardy said that advances such as these in Parkinson’s disease research could not have been made without the cooperation and dedication of the family members of this kindred. “It is important to emphasize the contribution of this particular family to the research effort,” said Dr. Gwinn-Hardy. “They have made a real difference to help others through their participation in research. Many other families likewise have made similar contributions, and in many, the effort is ongoing.”

NR

—Colby Stong

Suggested Reading
Gwinn-Hardy K. Genetics of parkinsonism. Mov Disord. 2002;17:645-656.
Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841.

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