Parkinson’s disease is considered a classic degenerative brain condition whose most-obvious symptoms arise from the loss of movement-regulating neurons near the brainstem. But it has long been clear that Parkinson’s causes other symptoms and affects other parts of the nervous system. Among its earliest symptoms are constipation and other gastrointestinal problems, and autopsy studies of people with Parkinson’s have found characteristic signs of the disease in intestinal nerve cells. Studies of people who died at different stages of the disease also suggest that the brain region known as the dorsal motor nucleus of the vagus, which connects to the gastrointestinal system, is affected very early in the disease.
Studies in animal models are now suggesting that this gastrointestinal connection is no coincidence, and that the disease may appear in intestinal nerve cells even before it reaches the brain.
“It makes sense that it could appear first in the autonomic nervous system, which is more exposed” to the environment, says Warren Olanow, a neurologist and Parkinson’s researcher at Mount Sinai School of Medicine in New York.
In the May issue of Human Molecular Genetics, senior investigator Robert Nussbaum and his colleagues at the University of California at San Francisco reported that they had engineered the genomes of a set of mice to include a mutant human gene that causes a rare familial form of Parkinson’s. The gene affects the protein alpha-synuclein, the major constituent of protein aggregates known as Lewy bodies and Lewy neurites, which collect inside neurons in affected brain areas in most forms of Parkinson’s. Alpha-synuclein’s normal function is unknown, but many researchers consider it a likely factor in most or all forms of the disease.
Nussbaum’s and others’ labs had created alpha-synuclein transgenic mice before, but these earlier versions had used a key genetic element known as a promoter from another gene. As a result the mutant alpha-synuclein had been expressed in fewer types of neuron than are normally seen in the human disease. In search of a more authentic model, Nussbaum’s team used the whole human alpha-synuclein gene, including its natural promoter element.
By the time they were three months old, these new alpha-synuclein-mutant mice showed extensive signs of gastrointestinal dysfunction. Nussbaum’s team also found alpha-synuclein-containing aggregates in the enteric neurons, those embedded in the lining of the gastrointestinal system. One subset of these mice, which bore an alpha-synuclein mutant gene known as A53T, developed motor abnormalities during the study’s three-month observation period, but only after developing enteric problems.
The finding in these mice, says Nussbaum, “doesn’t prove that Parkinson’s begins outside the brain, but it does provide additional evidence for that.”
Braak’s Hypothesis revisited
Most cases of Parkinson’s disease are not inherited, and although aging is clearly a factor, the disease strikes only a fraction of elderly people. This strongly implicates external, environmental factors as causes or triggers of the disease.
Based on autopsy studies that suggest a spread of Parkinson’s pathology from the dorsal motor nucleus to other brain regions, the neuroanatomist Heiko Braak, of Johann Wolfgang Goethe-University in Frankfurt, Germany, proposed in 2003 that Parkinson’s is triggered when a slow, hard-to-detect virus infects the gastrointestinal tract, via eating and drinking or by way of the nose and saliva. The intestines have their own “enteric brain” consisting of about a hundred million neurons. From these, Braak suggested, a virus could spread upward—much as the rabies virus does—via the vagus nerve to the dorsal motor nucleus and on to other vulnerable brain regions.
Nussbaum’s mouse model results suggest that a virus isn’t necessary. In fact, Nussbaum and other researchers suspect that the “infectious,” spreading agent in Parkinson’s is alpha-synuclein itself.
Like the amyloid-beta protein in Alzheimer’s disease, and prion protein in Creutzfeldt-Jacob disease, alpha-synuclein is short and relatively unstructured, with especially sticky elements that make it prone to cluster together. Researchers think that when a small cluster of such proteins has formed, it tends to pull in identical proteins in the vicinity, eventually forming long, insoluble stacks or fibrils, which may break into smaller pieces and then grow anew. In principle, the spread of these aggregates would resemble an infection. (See “Researchers Eye Role of Infectious Proteins in Neurodegenerative Disease”.)
Many researchers now suspect that the smaller alpha-synuclein clusters formed near the beginning of the aggregation process are the truly toxic forms of the protein, and that their toxicity will start to kill cells wherever the aggregation process gets out of control. That could happen if the normal systems that dispose of these aggregates within cells are weakened by an environmental factor, perhaps combined with the general weakening that comes with aging.
Nussbaum thinks that a host of environmental factors could serve as a trigger. “It could be a chemical; it could be something that causes inflammation; it could even be a particular set of bacteria or other microorganisms that are living in the gut and making toxic material,” he says. “And then if you are also genetically susceptible, perhaps because you overexpress alpha-synuclein even to a low degree, you tip a very delicate balance and end up with aggregation of alpha-synuclein.”
Support from other models
Pesticides are one environmental factor that epidemiological studies have clearly linked to Parkinson’s. The pesticide rotenone also is known to cause a Parkinson’s-like condition in rodents by damaging mitochondria within vulnerable neurons. Mitochondria are small, bacteria-like structures within cells that use oxygen to produce a basic form of chemical energy. When damaged by rotenone, mitochondria underproduce energy and overproduce cell-stressing oxygen free radicals. Either of these processes can severely stress a neuron and weaken its defenses against alpha-synuclein aggregation.
Last September, researchers in the lab of Timothy Greenamyre at the University of Pittsburgh reported that they exposed normal lab rats to low doses of rotenone for six weeks. The doses were too low to cause the usual, swift brain damage; the researchers wanted to see if a more subtle stress would show up first in the gastrointestinal system. They found that the rats—which otherwise seemed healthy—did lose some ability to coordinate digestion, and after a while, showed evidence of alpha-synuclein aggregates in their enteric neurons. “They very closely resembled what you see in the enteric nervous system in the human,” says Rob Drolet, lead author of that study and now a Parkinson’s drug developer at Merck & Co. in West Point, Penn.
Similarly, researchers at the Dresden University of Technology in Germany reported in January that low-dose rotenone delivered to the stomachs of mice induced alpha-synuclein formations in the enteric nervous system and later in some brain regions normally affected in Parkinson’s.
With the help of animal models like these, researchers hope to soon confirm the origin of Parkinson’s in the body and the manner in which it spreads. That in turn could enable neurologists to diagnose and treat the disease “much earlier in the process, when chances for success in neuroprotection are greatest,” says Drolet.