Evidence for Particulate Air Pollution to Encourage α-Synuclein Aggregation
Parkinson's disease and Lewy body dementia are synucleinopathies, forms of neurodegeneration characterized by the misfolding and aggregation of α-synuclein. Given an initial misfolding event, this pathology can spread from cell to cell through the nervous system and brain, one misfolded molecule encouraging others to also misfold in the same way. The resulting disruption of cell biochemistry kills neurons, particularly those involved in motor control. Here, researchers report evidence for particulate air pollution, known to correlate with increased risk of neurodegenerative conditions, to contribute to synucleinopathies by encouraging α-synuclein aggregation.
Researchers have uncovered a possible molecular connection between air pollution and an increased risk of developing Lewy body dementia (LBD). The team discovered that exposing mice to fine particulate air pollution (PM2.5) triggered formation of an abnormal alpha-synuclein (αSyn) strain, PM2.5-induced preformed fibril (PM-PFF). These toxic protein clusters shared key structural and disease-related features with those found in the brains of patients with Lewy body dementia.
The researchers also analyzed hospital data from 56.5 million U.S. patients admitted between 2000 and 2014 with neurodegenerative diseases. They focused on patients hospitalized for the first time with Lewy body-related conditions, and used data from the individuals' ZIP codes to estimate their long-term exposure to PM2.5. The scientists found that each interquartile range increase in PM2.5 concentration in these ZIP code areas resulted in a 17% higher risk of Parkinson's disease dementia and a 12% higher risk of dementia with Lewy bodies.
Exploring the biological reason for this association between exposure to PM2.5 and Lewy body dementia, the researchers then exposed both normal mice and mice genetically modified to lack the alpha-synuclein protein (αSyn-/- animals) to PM2.5 pollution every other day for a period of 10 months. "In normal mice, we saw brain atrophy, cell death and cognitive decline - symptoms similar to those in Lewy body dementia. But in mice lacking alpha-synuclein, the brain didn't exhibit any significant changes. We believe we've identified a core molecular link between PM2.5 exposure and the propagation of Lewy body dementia."