RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1
Copyright policy )RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1
Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.
- University of Minnesota System United States
- Boston Children's Hospital United States
- University of Minnesota Morris United States
- University of Minnesota United States
- MRC Protein Phosphorylation and Ubiquitylation Unit United Kingdom
Male, 570, MAP Kinase Signaling System, Molecular Sequence Data, 610, Down-Regulation, Nerve Tissue Proteins, Animals, Genetically Modified, Mice, PARKINSONS-DISEASE, CAG REPEAT, Cell Line, Tumor, Animals, Humans, Amino Acid Sequence, Molecular Targeted Therapy, Phosphorylation, Ataxin-1, SPINOCEREBELLAR ATAXIA, TRANSGENIC MICE, KINASE INHIBITORS, Nuclear Proteins, ALZHEIMERS-DISEASE, MODEL, Disease Models, Animal, Drosophila melanogaster, Ataxins, LOCUS DUPLICATION, HUNTINGTONS-DISEASE, Female, POLYGLUTAMINE-INDUCED NEURODEGENERATION, Mitogen-Activated Protein Kinases
Male, 570, MAP Kinase Signaling System, Molecular Sequence Data, 610, Down-Regulation, Nerve Tissue Proteins, Animals, Genetically Modified, Mice, PARKINSONS-DISEASE, CAG REPEAT, Cell Line, Tumor, Animals, Humans, Amino Acid Sequence, Molecular Targeted Therapy, Phosphorylation, Ataxin-1, SPINOCEREBELLAR ATAXIA, TRANSGENIC MICE, KINASE INHIBITORS, Nuclear Proteins, ALZHEIMERS-DISEASE, MODEL, Disease Models, Animal, Drosophila melanogaster, Ataxins, LOCUS DUPLICATION, HUNTINGTONS-DISEASE, Female, POLYGLUTAMINE-INDUCED NEURODEGENERATION, Mitogen-Activated Protein Kinases
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).123 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!