title: Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1.
abstract: Polyglutamine diseases are dominantly inherited neurodegenerative diseases caused by an expansion of a CAG trinucleotide repeat encoding a glutamine tract in the respective disease-causing proteins. Extensive studies have been performed to unravel disease pathogenesis and to develop therapeutics. Here, we report on several lines of evidence demonstrating that Nemo-like kinase (NLK) is a key molecule modulating disease toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in the protein ATAXIN1 (ATXN1). Specifically, we show that NLK, a serine/threonine kinase that interacts with ATXN1, modulates disease phenotypes of polyglutamine-expanded ATXN1 in a Drosophila model of SCA1. Importantly, the effect of NLK on SCA1 pathology is dependent upon NLK's enzymatic activity. Consistent with this, reduced Nlk expression suppresses the behavioral and neuropathological phenotypes in SCA1 knock-in mice. These data clearly indicate that either reducing NLK enzymatic activity or decreasing NLK expression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.
authors.affiliation: Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hyoungseok
authors.initials: H
authors.lastname: Ju
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kokubu
authors.forename: Tiffany W
authors.initials: TW
authors.lastname: Todd
authors.forename: Juliette J
authors.initials: JJ
authors.lastname: Kahle
authors.forename: Soeun
authors.initials: S
authors.lastname: Kim
authors.forename: Ronald
authors.initials: R
authors.lastname: Richman
authors.forename: Karthik
authors.initials: K
authors.lastname: Chirala
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Janghoo
authors.initials: J
authors.lastname: Lim
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067696:Ataxin-1; D000067528:Ataxins; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology; D002531:Cerebellum / Q000473:pathology; D002850:Chromatography, Gel; D004331:Drosophila melanogaster / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology* / Q000523:psychology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; C408347:Nlk protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases