They have found evidence that the gene normally acts to suppress an inflammatory response and, in turn, the production of neurotoxins in the brain. Those neurotoxins can otherwise spawn the damage to dopaminergic neurons that is characteristic of Parkinson's disease. The findings not only offer new insight into the causes of the disease, but also may point to new avenues for therapy, according to the researchers.
In its normal form, "the gene protects against Parkinson's," said Christopher Glass of the University of California, San Diego. "This system functions in the brain, and probably in other parts of the body, to protect from the deleterious effects of excessive inflammation." When the Nurr1 gene is disabled, as it is in those with the rare familial form of Parkinson's disease, it leads to a pattern of inflammation that is exaggerated in both magnitude and duration, he added.
The causes of most common forms of Parkinson's remain poorly understood, but the disease is generally associated with an inflammatory component involving cells known as microglia, the researchers explained. Those microglia act as sentinel cells, keeping a lookout for potential infection or tissue injury in the central nervous system. As for Nurr1, studies had found it plays an important role in dopaminergic neurons and that people with a rare mutant form of the gene produce too little of the protein it encodes, leading them to develop Parkinson's disease late in life.
Earlier reports also showed that Nurr1 operates in cells other than neurons, where its activity is increased by inflammatory factors. Glass and his colleague Kaoru Saijo, also of UCSD, suspected that Nurr1's roles outside of neurons might also be involved in Parkinson's disease. Indeed, they've now shown that Nurr1 limits the activity of pro-inflammatory neurotoxic mediators in microglia and in cells known as astrocytes, which serve as support cells to neurons. When Nurr1's activity is reduced, microglia launch an exaggerated inflammatory response that is amplified further by astrocytes. It is this overreaction that leads to the production of factors that ultimately kill dopaminergic neurons.
The findings suggest that inflammation may be an important general contributor to Parkinson's disease, which in the vast majority of cases has not been traced to any genetic cause, Saijo said. The researchers noted that while experts have grown to appreciate that Parkinson's disease has an inflammatory component, questions still remain about its role as a cause or consequence of the disease.
"We think if inflammation is not an initiating event, it is definitely a part of the process that could amplify the disease," Glass said. That's a key point moving forward, he said, because it suggests there should be further efforts to evaluate and test anti-inflammatory therapies in the treatment of Parkinson's. Treatments designed to interrupt the signals between microglia and astrocytes might hold additional promise for fighting the disease.
The new results may also have implications for the ultimate success or failure of stem cell therapies, Glass said. If the progression of Parkinson's disease is significantly influenced by inflammation as the researchers suggest, then any cell-based therapies designed to replace the dopaminergic neurons that are lost with new ones will also "have to deal with this process."