Quick: Is Parkinsons disease (PD) inherited, like Huntingtons disease, or sporadic, like most forms of breast cancer? In other words, is there a gene or genes that cause PD to run in families?
Until 1997 and 1998, neuroscientists unanimously agreed that PD cropped up spontaneously, with no parental help. Then two genes surfaced, one in 1997 called alpha-synuclein, the other, parkin, in 98. (See BioWorld Today, April 9, 1998, p. 1.)
In 97 and 98, recalled neuroscientist and PD clinician Michael Schlossmacher, it was found that when those genes are mutated, you can have a familial form of PD. Normally, its not inherited, not based on genetic abnormalities. In 95 percent of the cases, people walk into the clinic and have PD, with no family history and no gene at fault. So it was thought to be a sporadic disease.
With the discovery of those PD genes, people didnt really know what their products did, what their job is normally. And it was largely felt that these forms of inherited PD are not related to the sporadic garden-variety form of it. Like the Indian elephant [Elephas maximus] and the African elephant [Loxodonta africana], Schlossmacher analogized, are not really one and the same elephant.
An instructor and attending neurologist at Harvard-affiliated Brigham and Womens Hospital in Boston, Schlossmacher is co-principal author of an article in todays Science, dated June 28, 2001. Its title: Ubiquitination of a new form of a-synuclein by parkin from human brain: Implications for Parkinsons disease. Its senior author is Dennis Selkoe, founding director of the hospitals Center for Neurologic Diseases.
Our paper reports, Schlossmacher told BioWorld Today, the first biochemical link between two genes, which when mutated, can cause familial or inherited forms of PD. And the two proteins we found interact directly. Not only do they physically touch base with each other, but one modifies the other, and helps to eliminate it.
Parkin, he explained, is an enzyme, and a form of alpha-synuclein is its substrate the one material that has to be eliminated. Its known from sporadic PD that alpha-synuclein tends to accumulate in cells of affected people, even when theres no gene mutation. All along we knew there was something funny about this alpha-synuclein protein, that it tends to aggregate and accumulate, and slowly but surely destroys its cells. Now its thought that the parkin genes product encodes or helps to eliminate alpha-synuclein. So the issue is, if you cannot eliminate it efficiently, because the parkin gene is mutated, youll accumulate more of this alpha-synuclein substrate, and therefore the mechanism is not known yet cell toxicity ultimately leads to the death of the neurons.
Comparing Parkin, Synuclein In Normal, PD Brains
Schlossmacher and his co-authors set out to determine whether parkin interacts with alpha-synuclein in healthy human brains. We did a study in normal brains first, and could prove that the two interact, and that parkin helps to eliminate the alpha-synuclein. It does that by adding on ubiquitin, a small flag-like molecule, so the cell realizes it has to be degraded chopped up and discarded.
We then went to our Japanese co-authors, he recounted, who have collected some of the cases in brains of patients who had died with PD. Those brains are deficient in parkin, so have inherited PD and parkin deficiency. And when we studied those brains we could detect that this mechanism doesnt happen any more in the familial form of the disease. Indeed, the form of alpha-synuclein that is glycosylated actually accumulates in the brains of these patients.
In our in vitro study we first used brains from PD patients whose genes had large deletions where the missing half of the gene product reflected the missing half of the gene encoding parkin. We showed that not even the half that was supposed to be there was to be found. So it was a complete deficiency of parkin or parkin-like protein.
The neurological hallmark of Parkinsons disease is deficiency of the neurotransmitter dopamine. In fact, a PD patients response to medicinal dopamine replacement is diagnostic of the disorder.
Of the billions of neurons we have in our brains, Schlossmacher observed, a small subgroup of nerve cells is affected in PD. Those are the cells that synthesize dopamine. Virtually all PD patients lack dopamine in essential regions of the brain. And the mainstay of treatment is to replace the dopamine deficiency by drugs.
Nobody in the world yet knows, he pointed out, why dopamine metabolism, or the neurons that synthesize that chemical messenger in the brain, are so vulnerable to alpha-synuclein accumulation. Thats the million-dollar question, and hopefully in the next few years it will be unraveled.
The phenomenon is seen in many other neurological diseases of similar severity and one of them is Alzheimers disease [AD]. Accumulation of insoluble proteins, which have not been successfully eliminated from the cell, happen to cluster in different cell groups in different diseases. For instance, in Huntingtons disease its a different cell group than AD or PD have.
On Front Burner: Simple PD Risk Test
The biggest question now, Schlossmacher suggested, is whether that biochemical framework we studied also holds true for sporadic PD. Weve started to collect many of those PD brains, and were going to do an analysis to see whether thats true in sporadic PD, and whether well be able to develop a biological marker. There is no marker at this moment in time for PD. Hopefully we will find glycosylated synuclein in spinal fluid, to be able to tell people whether they have risk for the disease.
Its in our next plan to ultimately open up new treatment avenues. Certainly we can treat symptoms of PD, but we cannot halt or reverse the disease. I think if were lucky enough to have a pool of a particular form of alpha-nuclein that is targeted by parkin, and if we find that that correlates with PD activity, then we can target that to diminish the amount of it in the brain, or turn it over more rapidly. We dont yet understand the function of it or the effect of how it can be neurotoxic, but thats all a top priority on our front burner. Hopefully in six months well know more about it.