Out in California two decades ago, a bunch of heroin addicts tried shooting up a new synthetic designer narcotic they'd heard about. They ended up injecting a chemical toxin known as MPTP that sent four of them to the hospital with irreversible symptoms of Parkinson disease (PD).
MPTP (the acronym stands for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has since become a favored resource for creating animal models that faithfully mimic the chronic pathology of the human PD movement disorder.
"In PD," explained research neurologist Joseph Jankovic, "there is a loss of dopaminergic neurons in the substantia nigra - a part of the midbrain that contains these dopamine-secreting cells." Jankovic is director of the Parkinson Disease Center at Baylor College of Medicine in Houston. He is co-senior author of a paper in Nature Genetics, published online Dec. 23, 2002. Its title: "Mutations in NR4A2 associated with familial Parkinson disease." His co-senior author is Wei-dong Le, who heads Baylor's PD neurology research laboratory.
"Our article in Nature Genetics," Jankovic told BioWorld Today, "reports the discovery of two mutations in a gene that codes for a protein that is important for the development of the dopamine system. This gene was obviously a prime candidate for us to study in patients with PD, a disease in which the dopamine system is disturbed."
A Mutant Gene With A Difference
"As the NR4A2 gene was initially found and studied here at Baylor, we were in a unique position to look for any mutations," he observed. "We found two mutations in the gene's first exon in a subgroup of PD patients, out of 107 individuals we screened. If this study could be replicated, it might prove to be the most common gene mutation so far identified in PD. Currently," he pointed out, "there's really only one mutation that has been associated with Parkinson disease - namely, the alpha-synuclein mutations, but they are extremely rare and have been found in only one or two large families.
"There's another aberrant PD gene," Jankovic added, "the parkin mutation, which is common only in young individuals with the disease. But so far, no one has been able to find a mutation in patients with an otherwise typical onset of PD.
"There are at least two important implications from these findings," Jankovic observed. "First of all, is this gene mutation pathogenically related to PD? We think it is, based on the experiments we conducted to prove that this gene mutation is not just a simple polymorphism, but actually results in altered function. That would suggest - at least in the subset of patients with PD - that there might be a decreased or impaired development of the dopaminergic system, which may occur at birth, or even before birth. And as a result of age-related attrition in that system, these individuals who are born genetically predisposed to PD develop the symptoms much earlier than they would otherwise - in their 50s instead of 90s or 100s.
"The other implication," Jankovic went on, "is that, potentially mutant NR4A2 could be used as a diagnostic or prenatal test for PD. This mutation, when found, could then be considered a risk factor for development of the disease."
The Baylor co-authors had previously turned from human PD to its BTPD-toxin-induced animal imitators. "When we took a mouse and knocked out both of those NR1 genes that code for the development of the dopaminergic system," Jankovic recounted, "the animals died at birth, or shortly thereafter. If, however, we knocked out only one of the chromosome's two genes, we produced a heterozygote (with only one mutant parent). Those animals looked normal at birth. In fact only after their first few months of life did they begin to develop slowness of movement and behavioral changes that suggested parkinsonism. More important, biochemically and histologically, they showed evidence of dopaminergic deficiency.
"So these heterozygous animals, with NR1 single parent-inherited gene deficiency could be potentially used as models for PD," Jankovic said. "So far, all of the animal models used to study PD are acute models, produced by toxins such as MPTP. But our genetic model, for the first time, precisely simulates progressive neurodegenerative disorder and the hallmarks of familial parkinsonism."
As for the 94 sporadic, gene-free PD patients, "the cause of environmental insults to their dopamine system remains the 64-million-dollar question," Jankovic said. "A growing body of evidence," he noted, "proposes that numbers of environmental factors play a role. For example, exposure to certain pesticides and herbicides have been suggested, as PD appears to be very common in environments where these compounds are employed. Furthermore, the more frequently used weed killers and bug killers are biochemically similar to MPTP toxin, which we know causes loss of dopaminergic neurons. Also, the insecticide rotenone produces parkinsonism in animal models. Exposure to pesticides is one of the factors being intensively studied here. We're looking at a number of toxins - BMTP and the insecticide rotenone - and how they affect the dopaminergic system."
Nicotine? Caffeine? Yes Vs. PD
"There are some protective factors," Jankovic observed, "such as smoking, for example, and drinking coffee, which both appear to be associated with lower incidence of parkinsonism. Patients with PD are usually nonsmokers and often do not drink coffee. A number of epidemiological studies have shown that smoking might be neuroprotective, probably because nicotine actually causes release of dopamine. It produces a dopaminergic state in a way that may delay the onset of parkinsonian symptoms." Jankovic made the point, "That's just one hypothesis. I'm not trying to suggest that people should start smoking.
"Next, we would like to determine the frequency of the mutant genes in the general PD population - familial and sporadic," he volunteered. "So we are aggressively collecting DNA from patients with PD, and hope to screen 500 to 1,000 individuals. This may evolve into a multicenter study.
"The therapy for PD has improved dramatically in the last few years," Jankovic pointed out. "To my knowledge, specific NR1 receptor agonists are not available yet, but it's certainly an implication of our finding that if one can bypass this mutation and stimulate the healthy NR1 receptors by an agonist, that could potentially have a neuroprotective effect, and slow down progression of the disease," he concluded.