NpgRJ_NCHEMBIO_782 1..5

Oxidative stress, inflammation and a-synuclein overexpression1 confer risk for development of a-synucleinopathies— neurodegenerative diseases that include Parkinson disease and Lewy body dementia2. Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species3. Intraneuronal deposition of asynuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases2. Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate a-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses a-synuclein4. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable a-synuclein aggregation, leading to a pathologic cycle.