After nearly 50 years of focusing on dopamine, the brain transmitter system that fails in Parkinson’s disease, experts in the field are increasingly convinced of the need to consider other possible culprits to solve the riddle of this disabling neurodegenerative disorder. A protein called alpha-synuclein is at the top of the list.
“It’s time to abandon the ‘dopamaic’ view of the Parkinson’s universe,” says Anthony Lang, a Parkinson’s researcher at the University of Toronto, drawing a metaphor to the long-held but misguided view by first-century astronomer Ptolemy that Earth was the center of the celestial universe.
The shift is due in part to the growing realization that treating only the classic dopaminergic symptoms of the disease—tremor, stiffness and other movement problems—is simply not enough. Collectively, these symptoms are often referred to as “parkinsonism,” and they are the target both of drugs that replace dopamine and of surgical approaches such as deep brain stimulation (DBS). DBS involves implanting electrodes in a precise area of the brain, then using high-frequency electrical current to stimulate activity in a neural circuit known to be involved in Parkinson’s.
The problem with dopamine replacement therapy and surgical approaches such as DBS is that “all of the other aspects of Parkinson’s that are not dopamine-dependent are untouched,” says Mahlon DeLong of Emory University, who has spent his career mapping the dopamine circuit and pioneering surgical approaches, including DBS.
William Langston, director of the Parkinson’s Institute in Sunnyvale, Calif., has described Parkinson’s as an iceberg: dopamine-related symptoms represent the tip, while a much larger constellation of symptoms remains largely unrecognized. These symptoms, which can include sleep disorders, gastrointestinal and cardiac problems, and cognitive and emotional disturbances such as depression, anxiety and dementia, can seriously impact disability and quality of life.
“All this other stuff doesn’t even get labeled as Parkinson’s until the dopaminedependent symptoms are triggered, which is a fairly late process in the evolution of Parkinson’s pathology,” DeLong says.
The hallmark pathological characteristics of Parkinson’s, almost invariably seen in patients upon autopsy, are so-called Lewy bodies, which are sticky clumps comprised of alpha-synuclein that aggregate inside cells. Lewy bodies can show up not just in the substantia nigra, a brain region where dopamine cells die, but elsewhere in the brain and even elsewhere in the body.
An emerging view is that Parkinson’s may actually start in the gut and “work its way up through the nervous system via the vagal nerve, almost like a spreading virus or toxin,” says DeLong. The involvement of the vagal nerve, the main signaling highway for the autonomic nervous system that controls breathing, digestive processes, heart rate and other automatic body functions, may account for many of the nondopaminergic symptoms increasingly recognized as part of the Parkinson’s complex. The olfactory bulb, the brain’s center for processing smells, also appears to be affected in the earliest stages of the disease.
This model was actually first postulated by James Parkinson, for whom the disease is named, in his 1817 “Essay on the Shaking Palsy,” and has recently been championed in research published by Heiko Braak and colleagues at Goethe University in Frankfurt. According to the model, the substantia nigra is hit perhaps midway through the upward progression through the brain, followed by involvement of the cortex and emotional circuits, which could explain Parkinson’s-related dementia and other neuropsychiatric problems.
“If Braak is right and this disease starts much earlier in a different area of the brain, with the dopamine system only hit midway, we may be getting in there way too late [with therapy],” Langston says.
Many researchers have now trained their attention on alpha-synuclein. Mutations in the gene that encodes alpha-synuclein cause a rare inherited form of Parkinson’s, and just having extra copies of the normal gene is enough to produce symptoms. Upon autopsy, synuclein pathology is seen in about 90 percent of people who have “sporadic,” or non-genetic, forms of Parkinson’s.
To Michael K. Lee, a Johns Hopkins pathologist who studies synuclein, the protein is “guilty by association.” While there is no direct proof so far that synuclein causes sporadic Parkinson’s disease, “if your fingerprints are on the crime scene, then you must have something to do with it,” he says.
Not everyone is as convinced. “Alpha-synuclein is the tombstone, a marker of neurons affected in the disease process, but it may not be the cause of death,” points out Mayo Clinic geneticist Matt Farrer, whose own lab is heavily involved in synuclein research. “I don’t think we can look at Parkinson’s disease as purely an alphasynuclein disorder. That would be just as dangerous as thinking of it as purely a dopaminergic disorder.”
At least four major drug companies are already developing drugs targeted at synuclein, according to Langston. Others are trying to use RNA interference, a therapeutic technique that can selectively block gene transcription, to knock down the amount of synuclein.
“There are a number of compounds out there that have been shown to prevent synuclein aggregation, or even dissolve it, in vitro,” says Lee. “The question is, will they work in the brain?”
Farrer, despite his caution, is excited by the evolution under way in the field. “We’re finally making progress in understanding the root causes, finding targets for novel therapies, and making more appropriate models in which their efficacy can be judged,” he says. “These are fantastic advances for practitioners and patients … and, oh yes, drug companies, too.”