Chemicals in diesel exhaust can trigger the formation of toxic protein clumps and the death of nerve cells — hallmarks of Parkinson’s disease — by preventing the cell’s natural disposal mechanisms from working properly, a study in fish and human cells shows.
The findings also demonstrated that boosting these cellular recycling mechanisms with an approved leukemia medication, Tasigna (nilotinib), reduced the neuronal toxicity caused by diesel exhaust.
The study, “Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy,” was published in the journal Toxicological Sciences.
In addition to causing respiratory and heart diseases, long-term exposure to air pollution is increasingly implicated in the development of neurodegenerative diseases, potentially accounting for environmental factors that cause disease.
The main components of air pollution in urban environments come from diesel exhaust, and research in humans and animal models has suggested that diesel exhaust contributes to neurodegeneration and protein aggregation. But the mechanisms through which diesel exhaust chemicals cause these disease features remain unknown.
To address this further, researchers at the University of California, Los Angeles (UCLA) tested the chemicals from diesel exhaust on zebrafish, a fish species that have similar neuronal networks as humans. Zebrafish are well-suited to study environmental toxins, and their transparent larvae enable researchers to easily examine brain cells in living animals.
“Using zebrafish allowed us to see what was going on inside their brains at various time-points during the study,” Lisa Barnhill, a UCLA postdoctoral fellow and the study’s first author, said in a press release.
The team added chemicals from diesel exhaust to the water in which the zebrafish were grown. Exposure to these chemicals changed how animals were moving throughout the day and caused the death of nerve cells. Parkinson’s patients experience a loss in dopamine-producing neurons, but all neurons were being affected in the zebrafish.
After excluding problems in the proteasome — a machinery in cells that degrades proteins — as the cause of neuronal death, the researchers turned their attention to another process used by cells to clear out toxic accumulations of unwanted components: autophagy. This mechanism is used to recycle cellular components, including the toxic protein aggregates seen in neurodegenerative conditions, and its function is known to be altered in Parkinson’s.
Before being exposed to the chemicals, the fishes’ neurons had tiny sacs moving around that were carrying the damaged or old components to be destroyed. During the autophagy process, these sacs merge with another component in cells, called the lysosome, that is full of powerful degrading enzymes.
But after the chemical treatment, these sacs rose in numbers because they were no longer able to fuse with lysosomes. This meant that proteins and other toxic molecules were not being cleared out of cells properly, leading to nerve cell death.
The team then examined what this impairment in autophagy did to protein aggregation in nerve cells. Zebrafish do not have the alpha synuclein protein — whose aggregation into toxic clumps is a hallmark of Parkinson’s — but researchers found that exposure to the chemicals from diesel exhaust significantly increased the aggregation of another protein of the same family, synuclein gamma 1.
Finally, treatment with Tasigna, an approved leukemia therapy shown to increase autophagy in zebrafish models, was able to rescue nerve cell death in these animals, the team found.
“Although still in preliminary stages of investigation, this class of drugs has shown promise in several model systems and lends credence to the idea that impaired autophagy is a primary molecular mechanism of neurotoxicity in neurodegenerative disease,” the researchers wrote.
Overall, the findings suggest that exposure to air pollution, and particularly diesel exhaust, is able to induce features of Parkinson’s disease by impairing the normal functioning of the cells’ waste disposal. Yet, researchers believe this is not the only mechanism affected by diesel exhaust, as other studies also have reported increases in neuronal inflammation.
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