By David N. Leff
As the baby-boomer generation edges closer to confronting the degeneration — physical and mental — of impending old age, Social Security and retirement funds attract increased attention.
But besides concern over the post-employment burn rate of personal financial reserves, there's another asset that accelerates its expenditure as the so-called golden years set in. This is the body's one-time investment in non-renewable brain cells.
Parksinson's disease (PD) and Alzheimer's disease (AD) are the commonest of the neurodegenerative ailments that afflict the elderly. Both command heightened therapeutic research activity, in keeping with their expanding market, as well as their patient and family misery index. PD affects anywhere from 250,000 to 500,000 men and women in the U.S., but 1 percent of the population over 65 years of age.
The English physician James Parkinson (1755-1824) described in 1817 what he called "the shaking palsy," a diagnostic checklist of symptoms that, by and large, is still valid today:
"Involuntary tremulous motion, with lessened muscular power, in parts not in action, and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellects being uninjured."
These disabilities result from the brain's overdrawing its account of dwindling dopaminergic neurons in the cerebral substantia nigra. Those cells produce dopamine, a neurotransmitter that governs bodily movements and is lacking in parkinsonism and PD. It also involves metabolic disturbances in Alzheimer's disease.
A synthetic compound called levodopa generates dopamine in the brain and usually affords striking improvement early in treatment. Although levodopa has many severe shortcomings as a therapeutic, its anti-PD effects are sufficiently clearcut as to confirm a diagnosis of true Parkinson's disease, rather than parkinsonism from other causes.
In Japan, a woman of 43 had been diagnosed in her teens with all the symptomatic hallmarks of parkinsonism. Four other juvenile-onset patients first suffered the disability between the ages of 18 and 27.
Parkinsonism-Linked Gene Identified
At Keio University School of Medicine, in Tokyo, neurogeneticist Nobuyoshi Shimizu and his colleagues studied these five atypical patients and used positional cloning to identify a gene on the long arm of human chromosome 6, which they named parkin. Mutations in its 465-amino-acid protein, Parkin, apparently accounted for the precocious parkinsonism.
Their report appears in today's Nature, dated April 9, 1998, and is titled: "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism [AR-JP]."
"Although the rare AR-JP disease has been mostly described and defined in Japan," observed molecular geneticist Robert Nussbaum, "I have heard anecdotally that there are other families in Europe with a very similar phenotype that map to the same chromosome in the same chromosomal region as the juvenile parkinsonism in Japan."
Nussbaum is chief of the Laboratory of Genetic Diseases Research at the National Human Genome Research Institute, in Bethesda, Md. He wrote an editorial accompanying the Nature paper, titled: "Putting the Parkin into Parkinson's."
"AR-JP," Nussbaum told BioWorld Today, "is not PD." He added, "It's called parkinsonism because from a symptomology point of view, the two are the same. Both types of patients lack dopaminergic neurons in the substantia nigra, so they have the same kind of movement disorder.
"But the pathological process that leads to the loss of those neurons," he went on, "is different between PD and AD-JP, simply based on the presence or absence of Lewy bodies.
"Lewy bodies," Nussbaum explained, "are protein aggregates of some kind, found as inclusion bodies in the cytoplasm of substantia nigra neurons. They're abnormal, and we don't know whether they're involved in the underlying disease process, are just a marker for it, or whether they themselves are actually toxic and pathogenic."
The Japanese disease, Nussbaum pointed out, is distinguished not merely by its teens-to-young-adult onset, but by its total absence of Lewy bodies. "What's more," he added, "classical PD is due to a deficiency of the Parkin protein, whereas the autosomal dominant version is due to the presence of an abnormal protein. It's a real distinction that's worth making."
He made the point that "most people with PD don't have mutations in the parkin gene, but that doesn't mean that the Parkin protein isn't playing a role in some way in the development of the disease. That is intriguing."
Lewy Bodies, alpha-synuclein, Enter PD Picture
Parkin was the second PD-related gene to be discovered; the first was alpha-synuclein, found by Nussbaum last summer and located on the long arm of human chromosome 4. (See BioWorld International, March 4, 1998, p. 1.)
"Alpha-synuclein," he recounted, "is a fairly abundant neuronal protein of unknown function, in which we have identified two missense mutations in families with early-onset PD — with Lewy bodies. The importance of this finding," he continued, "is that, yes, it's nice to know that there's a particular gene that can cause PD in these two rare families.
"But the real significance of that work," Nussbaum observed, "is that when we stain Lewy bodies from patients who don't have mutations in alpha-synuclein, their Lewy bodies are full of alpha-synuclein."
Now for the PD-AD connection: "When we originally identified alpha-synuclein, it was because people were isolating senile neuritic plaques from the brains of Alzheimer's disease patients, and looking at the proteins contained in those plaques. One of those proteins was a peptide called NAP — non-amyloid peptide. When they sequenced it, it turned out to be a fragment of alpha-synuclein, so there's some connection to AD."
Nussbaum foresees that "one area people are going to look at now very closely is what role does Parkin play in normal neuronal function and support. We don't know," he said.
"For example," he went on, "is the Parkin trapped in Lewy bodies, and therefore not available? Could it be a secondary loss of Parkin that's killing the neurons in PD?"
Nussbaum is placing his bets on animal models to elucidate some of these vital unknowns. Finally," he concluded, "if you have a knockout mouse that lacks Parkin and develops PD, or parkinsonism — loss of neurons — that would be an excellent model system in which to study neuroprotective drugs." *