Your gut may play a pivotal role in preventing the onset of Parkinson's disease…Researchers at the University of Iowa have found that the gut may be key to preventing Parkinson's disease. Cells located in the intestine spark an immune response that protects nerve cells, or neurons, against damage connected with Parkinson's disease. Acting like detectives, the immune intestinal cells identify damaged machinery within neurons and discard the defective parts. That action ultimately preserves neurons whose impairment or death is known to cause Parkinson's.
"We think somehow the gut is protecting neurons," says Veena Prahlad, assistant professor in biology at the UI and corresponding author on the paper published Aug. 30 in the journal Cell Reports. Parkinson's disease occurs when neurons--nerve cells--in the brain that control movement become impaired or die. Normally, these neurons produce dopamine, and when they are damaged or killed, the resulting dopamine shortage causes the motor-control problems associated with the disease. Scientists have previously linked Parkinson's to defects in mitochondria, the energy-producing machinery found in every human cell. Why and how mitochondrial defects affect neurons remain a mystery. Some think the impaired mitochondria starve neurons of energy; others believe they produce a neuron-harming molecule. Whatever the answer, damaged mitochondria have been linked to other nervous disorders as well, including ALS and Alzheimer's, and researchers want to understand why.
Prahlad's team exposed roundworms to a poison called rotenone, which researchers know kills neurons whose death is linked to Parkinson's. As expected, the rotenone began damaging the mitochondria in the worms' neurons. To the researchers' surprise, though, the damaged mitochondria did not kill all of the worms' dopamine-producing neurons; in fact, over a series of trials, an average of only seven percent of the worms, roughly 210 out of 3,000, lost dopamine-producing neurons when given the poison.
In a paper published in the academic journal Nature Communications, ISU scientists identified a protein called Prokineticin-2 (PK2) that may protect brain cells and is expressed with greater frequency in the early stages of Parkinson's disease. "The neurons use PK2 to cope with stress. It's an in-built protective mechanism," said Anumantha Kanthasamy, a Clarence Hartley Covault Distinguished Professor in veterinary medicine, the Eugene and Linda Lloyd Endowed Chair of Neurotoxicology, and chair of biomedical sciences at Iowa State. Kanthasamy, one of the paper's lead authors, has been working to understand the complex mechanisms of Parkinson's and searching for a cure for the past two decades.
Prokineticin-2 stimulates the neurons to produce more mitochondria, the part of the cell that produces energy. The resulting improved energy production helps neurons withstand the effects of the disease. Better understanding of Prokineticin-2 could turn up a means of slowing development of the disease or lead to new therapies, Kanthasamy said. For instance, there may be ways to stimulate more production of the protein or protein analogs to bind with its receptors on neurons, he said.
The research team took a multidisciplinary and integrated approach to studying Parkinson's disease. The study was funded by a grant from the National Institutes of Health to Kanthasamy and Arthi Kanthasamy, a professor of biomedical sciences and Anumantha's spouse. Six graduate students in Kanthasamy's lab also contributed to the study, including co-first authors Richard Gordon and Matthew Neal, as well as researchers at other institutions. The scientists studied cultured brain cells, a rodent model and post-mortem human brains to track changes brought on by Parkinson's disease, and they confirmed a high expression of Prokineticin-2 in each facet of the study. It was this team effort that resulted in a comprehensive finding, Arthi Kanthasamy noted. The discovery prompted the research team to investigate more thoroughly. "Of the thousands and thousands of factors we tracked in our experiments, why was this protein expressed so highly?" Arthi Kanthasamy said. Finding the answer to that question poses a challenge that will take time to overcome, but the potential appears to be significant, she said.
Leading-edge research by the team of professor Patrik Verstreken (VIB-KU Leuven) has shown for the first time that a malfunctioning stress-coping mechanism in the brain is at the root of Parkinson's disease. Genetic mutations that cause Parkinson's disease can prevent synapses - the junctions between neurons where electrical signals are transmitted - from coping with the stress of intense brain activity. This damages the synapses, which in turn disrupts the transmission of brain signals. Building on these findings, the scientists hope to correct the dysfunction and find strategies to re-establish normal synaptic communication. The results are published in the leading trade journal Neuron.
Professor Patrik Verstreken (VIB-KU Leuven) specializes in brain research, with a particular interest in synapses, the place where neurons contact one another and transmit signals. In various brain disorders - like Parkinson's disease - communication at these synapses is impaired. The new research identifies an important cause of this disruption. "Synapses have to transmit an enormous amount of electrical signals. Some neurons will fire more than 800 of those signals in just one second. We have discovered that synaptic contacts have developed special mechanisms to deal with such a 'barrage' of signals. However, if one of these mechanisms doesn't function properly, cellular stress is accumulated. This causes damage to the synapses and ultimately leads to neurodegeneration."
Maintaining synaptic function
Professor Verstreken's team investigated different types of coping mechanisms and uncovered that one type is disrupted in Parkinson's disease. This aberration involves different known genetic factors and affects specifically synapses. "Our work is the first to implicate dysfunctional synapses so profoundly in Parkinson's. After using mostly fruit flies to understand the disease mechanism it will now be interesting to see whether an identical stress-coping mechanism is disrupted in human patients as well. Our collaborators at the European Neuroscience Institute in Göttingen led by Ira Milosevic already made very similar discoveries in mouse neurons. In any case, this research tells us that it is absolutely critical to find strategies to maintain synaptic function in treating this disease."
Building on the results of this research, the scientists want to find out how universal the stress-coping mechanism is disrupted in Parkinson's disease. "Next, we hope to correct the dysfunction caused by the Parkinson mutations and identify strategies that might re-establish normal synaptic communication. Reactivation of the coping mechanism, for instance, might also repair the damaged synapses. Of course, this requires additional research."
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