By David N. Leff
Go into a pet shop and ask to see a male Poephila guttata. The knowledgeable salesperson will show you a small, red-beaked, neatly striped gray or albino bird, better known as the zebra finch.
What these cute creatures have to do with Parkinson's disease (PD) is a tantalizing stretch. Before a young finch bursts into song, it has to learn the rapid-fire, finch-specific courtship vocalization from its parent and peers.
A protein called synelfin in the bird's brain supposedly helps in this song learning. The synelfin molecule's amino-acid sequence is homologous to the human protein a-synuclein. The single point mutation in the human a-synuclein gene -- from an A base to a G, thus replacing an alanine amino acid with a threonine -- corresponds to the zebra finch's genome.
The overall similarity suggests to neuroethologists that human a-synuclein may play a part in human memory and learning.
What's more, very recent research, reported in today's Science, dated June 27, 1997, bears the pointed title: "Mutation in the a-synuclein gene identified in families with Parkinson's disease [PD]."
Parkinson's, like Alzheimer's, is a disease of the elderly. Right? Only partly.
A small but meaningful fraction of the patients diagnosed with these neurodegenerative afflictions are stricken in the prime of life -- in their 30s, 40s and 50s, rather than the 60s and 70s. These early onset cases confirm that PD, of in which the cause remains a mystery, has a hereditary component, as well as presumed environmental etiology.
Tracing the likely link between PD and mutant a-synuclein, as announced in Science, relied on genotyping members of two extended families, one Italian, the other Greek, with numerous early onset, familial PD members. (See BioWorld Today, Nov. 15, 1996, p. 1.)
"Back in November," said the Science paper's lead author, psychiatrist/molecular geneticist Mihael Polymeropoulos, "we reported that we had located a gene responsible for PD. It resided on the long arm of human chromosome 4, in an area of about 60 million base pairs of DNA length.
"Since then," he told BioWorld Today, "we have narrowed down the region, identified a gene in it, a mutation in the gene, and seen this mutation in four unrelated families with PD."
This a-synuclein gene, Polymeropoulos continued, "is about 450 base pairs long. Its normal function is not known, but we do know that its expressed protein, synuclein, localizes in the brain of various species, including humans. We also know that most probably it's associated with the nerve terminals, the synapses."
How Zebra Finches Escape PD
He noted one more nugget of knowledge about the gene: "It was isolated from protein material extracted from the amyloid plaques of patients with Alzheimer's disease. So we know that the a-synuclein gene product is a component of these senile neuritic plaques." Polymeropoulos added: "The only functional data are experiments showing that the homologue of the a-synuclein gene in birds is associated with song-learning, which is very intriguing."
Which raises the question: Why then don't zebra finches come down with PD? One answer: Because their life span is so short, they don't have time to develop the advanced-age malady.
That alanine-to-threonine switch also corresponded to the mutations found in the Italian and Greek kindreds.
Polymeropoulos and his co-authors looked first at the large Italian family, which numbered about 500 individuals, over 12 generations. Some had emigrated from Italy to the U.S. a century ago, and more than 60 family members on both sides of the Atlantic are known to have had PD.
Of these, he recounted, "We were able to ascertain and get DNA samples from 11 patients. All but one carried the threonine mutation. Three of five unrelated Greek families that we looked at next carried the exact same gene alteration."
So far, the mutant synuclein protein lurks only in the brains of people with the early onset, familial form of PD. "We looked at 50 people of Italian descent who had the sporadic illness," Polymeropoulos recalled, "but we did not see this particular mutation.
Now Meet The Lewy Body
Just as amyloid plaques are the distinguishing neurobiological feature of Alzheimer's disease, a comparable hallmark in Parkinson's, Polymeropoulos pointed out, "is the presence of Lewy bodies."
"These are cytoplasmic inclusions in the neurons of PD patients," he explained. "Some of the patients also develop amyloid plaques in their brains, and a mental disorder called Lewy-body dementia."
Little is known about Lewy particles. "No one has yet looked for them in the synuclein protein," Polymeropoulos said. "Although they are found in other neurological disorders, Lewy bodies are the sine qua non of PD, in both its early onset familial, and late-onset sporadic, forms. If you don't see Lewy bodies, no matter what the clinical picture, it's not to be called typical PD."
Polymeropoulos heads the gene-mapping unit in the Laboratory of Genetic Disease Research at the National Institutes of Health National Human Genome Research Institute (NHGRI), in Bethesda, Md.
His PD project, using data from NHGRI, came up with three "firsts":
· "One, we reported the first genetic evidence for Parkinson's," he said, "which sets the stage for people to look into the inheritance of the disease.
· "Two, it's the first time we have a clue as to PD causation. Everything we had before was symptom-oriented.
· "Three, the mechanism we have proposed -- that these mutant proteins assume an abnormal structural conformation, and self-aggregate -- offer very interesting ideas for drug discovery."
He elaborated: "If indeed the abnormal protein tends to aggregate, to clump, it will form the nucleation point for Lewy bodies to form. It is conceivable that drugs could be developed to inhibit this aggregation."
Meanwhile, in the here-and-now, he suggested an immediate pay-off from the research to date:
"Knowing the mutation," he observed, "a genetic test becomes very simple: You just need a little blood, the PCR reaction, and we know who has the mutation or not.
"The question will be: Who should be tested? The answer: People who are at risk, defined as members of families with this early onset, severe illness.
"Why would that be useful? Their treatment is not going to change. The only thing that would be useful is that these people, anonymously and under protocol, participate in clinical studies of prevention. This is our first opportunity to identify individuals at risk long before they develop PD symptoms." *
Potential Putative Parkinson-Prion Connection
At a news conference in the National Press Club in Washington Thursday, psychiatrist/molecular geneticist Mihael Polymeropoulos answered a question about whether the Parkinson's disease mutant a-synuclein gene (see main story, beginning on p. 1) could be linked to prion diseases, such as mad cow and Creutzfeldt-Jakob:
"If the abnormal conformation of the protein is the correct mechanism, you could have that conformation without the mutation, as in prion diseases.
"There are two ways you can acquire these infectious prions: One is to eat them from an animal that already has this abnormally conformed protein in their meat. Or else, you can inherit a mutation in your own prion protein, which you carry on chromosome 20. This protein actually takes normal protein material and makes it behave in an abnormal conformation. Then you develop the same kind of encephalopathy, the severe illness, as you do with prion disease."