Parkinson's Disease

M.H. Polymeropoulos, C. Lavedan, E. Leroy, S.E. Ide, A. Dehejia, A. Dutra, B. Pike, H. Root, J. Rubenstein, R. Boyer, E.S. Stenroos, S. Chandrasekharappa, A. Athanassiadou, T. Papapetropoulos, W.G. Johnson, A.M. Lazzarini, R.C. Duvoisin, G. Di Iorio, L.I. Golbe, R.L. Nussbaum, "Mutation in the *-synuclein gene identified in families with Parkinson's disease," Science, 276:2045-7, June 27, 1997. (Cited in more than 250 papers since publication) Comments by Robert L. Nussbaum, chief of Genetic Disease Research Branch, National Human Genome Research Institute Robert L. Nussbaum Sometimes it seems like research progress hits a wall. That was the case in the early '90s with Parkinson's disease, remembers Robert L. Nussbaum. "There was this general feeling that the basic, underlying cause still had not been discovered," Nussbaum notes. Parkinson's patients and their families got impatient. Then they got organized. Zack Hall, then the director of the National Institute of Neurological Disorders and Stroke, convened a conference to assess the field's state and asked Nussbaum, who had never studied the disease, to present a geneticist's viewpoint. In preparation, Nussbaum immersed himself in the literature and found some "striking" things. Scientists studying Parkinson's had all but dismissed genetic contributions in favor of environmental causes. "It was absolutely true that all the previous twin studies did not support a strong genetic contribution to common, typical Parkinson's," he explains. However, he also noted several caveats, most notably that a few families had highly inherited autosomal-dominant, early-onset Parkinson's disease. Those families represented an opportunity, Nussbaum noted in his talk. "When you see an autosomal-dominant or recessive Mendelian form of a common disease that has an earlier onset, this suggests that there is a single gene that is probably involved in some way." Following Nussbaum's talk, geneticist Roger C. Duvoisin of Robert Wood Johnson Medical School in Piscataway, N.J., approached Nussbaum and mentioned that he, colleagues Larry Golbe and William G. Johnson, and geneticist Giuseppe Di Iorio of Naples, Italy, had been collecting data and DNA from the largest family Nussbaum mentioned. However, the group had difficulty getting support to do genotyping and linkage analysis on the Contursi, Italy-based clan. "I just thought this family was too important," Nussbaum notes. "So I volunteered our services." Nine days after National Human Genome Research Institute scientists began their linkage analysis on chromosome 4, they found a candidate region. As they compared family member after family member, they realized why previous analysis had been difficult--a "red herring" member had inherited a different allele from the other side of the family. They next homed in on a candidate gene on chromosome 4q. "Sitting right in the middle of that region was a gene that I had never heard of, called *-synuclein." That gene had first been found by Tsunao Saitoh, a University of San Diego, La Jolla, researcher who had identified it while analyzing proteins in amyloid plaques, the tangles associated with Alzheimer's disease.1 However, the literature on the gene halted abruptly, after Saitoh was shot and killed in an unsolved homicide. "His lab was devastated, and they stopped working on it." Nussbaum's lab was excited about the possible genetic link between Alzheimer's and Parkinson's. "When you're looking for a candidate gene in a region that's that large, you'll take anything that even remotely has a biological rationale," Nussbaum explains. They easily sequenced the gene and confirmed that it was, indeed, the one that was mutated in the Italian family. David F. Clayton and wife Julia M. George, associate professors of cell and structural biology at the University of Illinois, Urbana, had found the equivalent orthologue in zebra finches and determined that it played a role in song acquisition.2 "Two groups in completely unconnected areas converged on essentially the same gene," Nussbaum comments. To dissect the protein's role in Parkinson's, Nussbaum's lab looked for antibodies to it in Lewy bodies, aggregations on Parkinsonian brains. "The Lewy bodies lit up like light bulbs," Nussbaum recalls. "*-synuclein appears to be to Lewy bodies what ß-amyloid is to Alzheimer's plaques." That finding brought Parkinson's disease "into the fold" of other neurodegenerative diseases. "Many of these neurodegenerative disorders have a final common pathway," Nussbaum notes. "The players may be different, but maybe the processes are similar." Researchers still must tease out whether *-synuclein's presence in Lewy bodies is a cause or an effect of Parkinson's. "If it's causative, even without a mutation, why is it going into those aggregates? Is it a bystander that's getting damaged by some other process?" he asks, noting that much about the gene and its product remains a mystery. "We don't know anything about *-synuclein processing. We don't know the structure of *-synuclein once it gets into a Lewy body. If *-synuclein is being abnormally processed, or is being damaged in common forms of Parkinson's, then how and why and what is the damage coming from? If there are genetic or environmental contributions, what are they?" Nussbaum concludes. 1. K. Ueda et al, "Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease," Proceedings of the National Academy of Sciences, 90:11282-6, 1993. 2. J.M. George et al., "Characterization of a novel protein regulated during the critical period for song learning in the zebra finch," Neuron, 15:361-72, 1995.

Parkinson's Disease

Interested in reading more?

Become a Member of