“We think this is a new player in the game,” he continued. “Because the vesicles formed by this gene are present in other neurons besides the substantia nigra, it has a potential to explain the various effects of Parkinson’s disease as it progresses from being a sleep disorder to a motor disorder to a disorder of higher functioning.”
This particular mutated gene is rare—Deng and Siddique have found it in several families in China and North America—as are the others known to cause Parkinson’s. The Northwestern team has found no one who carries the mutation and does not develop the disease in old age. Still, it will account for relatively few cases of the disease overall. The importance of the discovery is evidence that this specific set of symptoms is due to malfunctioning dopamine vesicles.
“Theoretically, we can improve that vesicle movement,” Deng told me, emphasizing the practical relevance of the discovery. And, indeed, a small molecule called NAB2 that promotes dopamine trafficking has recently been shown to reverse dysfunction in isolated neurons sampled from some patients with Parkinson’s disease.
“Understanding this gene, and how it can lead to diseases, can help all kinds of people who may not have this particular mutation,” Beck concurred.
And understanding the disease at this level—as one of the slight malfunctioning of one type of vesicle in a tiny part of the brain—it becomes less intuitive that the disease is the product of being punched in the head. Repetitive trauma certainly does damage brains, most often in a global way, as in the traumatic encephalopathy that plagues the NFL. A CT scan of Ali’s in 1983 showed evidence of this: Ali’s brain was slightly shrunken, and the fluid-filled ventricles enlarged. His physician at UCLA at the time, called it “dementia pugilistica.” (A circular appraisal, Latin for the dementia that happens as a result of being hit in the head.)
“It's been known for a long time that boxers are disposed to dementia pugilistica,” Siddique told me this week. “I don't know Ali's clinical state, but I don't believe he was demented. He had Parkinson's disease, and some people think it's because of head trauma. As a neurogenetecist, I'm prejudiced to say that people have a certain proclivity that resides at the genetic level which predisposes them to environmental insults—whether they be pesticides, well water, living in rural areas, or trauma, possibly.”
The National Parkinson's Foundation does list head trauma to be a possible factor in Parkinson's, along with some insecticides and herbicides. The organization cites an adage to capitulate the limits of our understanding: “Genes load the gun, and environment pulls the trigger.”
The same could be said of most things in life.
Many more genetic linkages will likely be discovered in coming years, affecting many points in the process by which dopamine is released from nerve cells. Inside this man who was an icon of power, it may simply have been the case that these tiny vesicles couldn't make it to the surface. Multiple different problems might have been responsible for that. His symptoms may also have been caused by another, totally different process within his nerves that impaired his dopamine system. Some mutations linked to Parkinson’s disease (without Lewy bodies) affect the function of mitochondria. Other patients with the same symptoms have impairments in recycling of vesicles, but not in transport or mitochondrial function. A vaccine is being tested in Austria that would target a protein called alpha synuclein, which binds to vesicles and impairs them (and some researchers believe may be infectious). To treat these conditions the same way, as we do now, is like treating a headache and a sprained ankle the same way, with Tylenol.
One day, these causes of Parkinson's disease (syndrome) stand to be understood as different diseases, treated differently. The name Parkinson’s disease may well be forgotten long before the name Muhammad Ali.