Several neurological disorders, including spinocerebellar ataxia type 1 (SCA1), are caused by a toxic build-up of mutant proteins. To identify targets for SCA1, this study used parallel human cell-based and fruitfly genetic screens to show that downregulation of components of the RAS–MAPK (mitogen-activated protein kinase)–MSK1 (nuclear mitogen- and stress-activated protein kinase 1) pathway decreased mutant ataxin 1 levels and suppressed neurodegeneration in fruitflies and mice. Pharmacological inhibition of the pathway also decreased ataxin 1 levels, which suggests that it is a new target in SCA1. These methods could be used to identify targets for other neurodegenerative disorders with similar pathogenic mechanisms.
References
Park, J. et al. RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 29 May 2013 (10.1038/nature12204)
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Charlotte, H. Identifying pathogenic pathways. Nat Rev Drug Discov 12, 506 (2013). https://doi.org/10.1038/nrd4061
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DOI: https://doi.org/10.1038/nrd4061