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Identification of a small molecule that selectively activates alpha-synuclein translational expression

Publication TypeJournal Article
Year of Publication2012
AuthorsRoss, NT, Metkar, SR, Le, H, Burbank, J, Cahill, C, Germain, A, Macpherson, L, Bittker, J, Palmer, M, Rogers, J, Schreiber, SL
Date Published2012/01/09

Alpha-synuclein is a protein implicated in the pathogenesis of neurodegenerative alpha-synucleinopathies including Parkinson’s disease (PD), the most prevalent movement disorder in humans. Evidence suggests that misregulation of alpha-synuclein translation plays a clear role in the pathology of this disease. We report the outcome of a high-throughput chemical library screen to identify novel, nontoxic, and selective small-molecule activators of alpha-synuclein expression, which will aid understanding of the role of alpha-synuclein in PD and other neurodegenerative diseases. Of the 303,224-screened compounds, 22 hits were identified as activators of alpha-synuclein expression and subsequently validated to confirm their activation activity and selectivity. One of these compounds (ML163) displayed greater than 100-fold selective activation of alpha-synuclein expression compared with a related system and is inactive in a control system at the highest tested dose. Our results indicate that ML163 has a drug-like structure with no obvious chemical liabilities, excellent solubility, and stability in aqueous conditions. This new probe should be very useful in future cell-based investigations and in vivo studies of alpha-synuclein expression.