The Molecular Mechanisms of Diesel Exhaust Neurotoxicity: Autophagy as a mediator of Parkinson's disease risk

Parkinson’s disease is the second most common neurodegenerative disorder behind Alzheimer’s disease and is characterized by the loss of dopaminergic neurons in the substantia nigra. The pathological hallmark of Parkinson’s disease is the accumulation of insoluble aggregates called Lewy bodies which contain the protein alpha synuclein. Because the vast majority of disease cannot be attributed to genetics alone, there is significant interest in environmental modifiers of disease risk. Epidemiological evidence is highlighting an association between long-term exposure to air pollutants and Parkinson’s disease risk. This project explores the mechanisms of toxicity that may link exposure to air pollutants and Parkinson’s disease by addressing how diesel exhaust, a major contributor to urban air pollution, may induce neurotoxicity by upregulating gene expression, inhibiting protein turnover, and inducing neuroinflammation. In human cell culture, treatment with diesel exhaust particulate extract is shown to induce gene expression by upregulating promoter activity. In rat neurons and developing zebrafish larvae, synuclein protein is seen to be elevated after exposure. Using a zebrafish model for neuronal toxicity, it has been determined that exposure to diesel exhaust particulate extract causes a significant decrease in neuron number. Both the elevated protein levels and the neurotoxicity have additionally been shown, at least in part, to be due to reduced autophagic flux. When taken together, it can be seen that exposure to traffic-related air pollution can cause synuclein dysregulation, induce neuronal toxicity, and disrupt proteostasis in ways that contribute to neurotoxicity in vivo. Such dysregulation may, in part, explain how long-term exposure to traffic-related air pollution increases Parkinson’s disease risk and opens up new avenues for exploring disease-modifying therapeutics that may mitigate environmental toxin exposures and promote neuroprotection