New research, published in the journal Science Signaling, details the mechanism through which exposure to manganese can trigger protein misfolding in the brain — which may, in turn, lead to Parkinson’s-like symptoms. The findings may enable an earlier diagnosis of the neurological condition.
In the human body, manganese aids blood sugar regulation, bone formation, and immunity.
However, exposure to excessive levels of manganese may trigger Parkinson’s-like neurological symptoms.
Manganese builds up in the basal ganglia area of the brain.
Researchers have known about these links between manganese and Parkinson’s for decades, but new research helps elucidate the mechanisms behind these associations.
Anumantha Kanthasamy, the Linda Lloyd Endowed Chair of Neurotoxicology at Iowa State University in Ames, led the
Parkinson’s disease is characterized by clumps formed by
Kanthasamy and colleagues set out to investigate how these misfolding proteins might interact with manganese to trigger the progression of Parkinson’s.
To do so, they examined data from mice and blood serum samples collected from eight welders. As a group, welders have a higher risk of prolonged manganese exposure. The research also examined a control group of 10 people.
The analyses revealed that welders with exposure to manganese had higher levels of misfolded alpha-synuclein, which puts them at a higher risk of Parkinson’s.
Additional cell culture tests showed that misfolded alpha-synuclein was secreted through small vesicles called exosomes into the extracellular space. In other words, the vesicles enabled the proteins to travel from cell to cell and further spread the misfolded protein.
The scientists also isolated alpha-synuclein-containing exosomes from alpha-synuclein-expressing cells that had exposure to manganese and delivered them to a brain area in the mice called the corpus striatum. This induced Parkinson’s-like symptoms in the mice.
Manganese seemed to accelerate the “cell-to-cell transmission” of alpha-synuclein, which, in turn, led to neurotoxicity. Kanthasamy and colleagues explain:
“Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.”
“[W]e identified a possible mechanism involving the exosome-mediated, cell-to-cell transmission of [alpha-synuclein] during exposure to the environmental neurotoxicant,” write the authors.
According to the National Institutes of Health (NIH), around 50,000 individuals in the United States receive a diagnosis of Parkinson’s each year, and 500,000 people currently live with the condition.
Though the condition does not yet have a cure, diagnosing it earlier may prevent irreversible brain damage and help accelerate human clinical trials of new drugs.
The results that Kanthasamy and colleagues have just published may help scientists devise a new diagnostic test for Parkinson’s that could detect the disease much earlier on. The results may also help scientists test how effective new Parkinson’s drugs are.
“As the disease advances, it’s harder to slow it down with treatments,” Kanthasamy says. He adds: “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”
However, the study authors also caution that their findings are still experimental, and that such a diagnostic test may not be available for years.