title: RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jeehye
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Qiumin
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Nissa
authors.initials: N
authors.lastname: Mollema
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Diaz-Garcia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gallego-Flores
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hsiang-Chih
authors.initials: HC
authors.lastname: Lu
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Sarita
authors.initials: S
authors.lastname: Lagalwar
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Duvick
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yoontae
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Paymaan
authors.initials: P
authors.lastname: Jafar-Nejad
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Layal S
authors.initials: LS
authors.lastname: Sayegh
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
authors.forename: J Simon C
authors.initials: JSC
authors.lastname: Arthur
authors.affiliation: Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000067696:Ataxin-1; D000067528:Ataxins; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010766:Phosphorylation; D055550:Protein Stability / Q000187:drug effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000378:metabolism* / Q000473:pathology*; D019076:Transgenes; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins