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J Neurosci ; 33(22): 9328-36, 2013 May 29.
Article in English | MEDLINE | ID: mdl-23719801

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.


Subject(s)
Drosophila melanogaster/physiology , Heredodegenerative Disorders, Nervous System/genetics , Heredodegenerative Disorders, Nervous System/pathology , Mitogen-Activated Protein Kinases/physiology , Peptides/physiology , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/pathology , Animals , Animals, Genetically Modified , Ataxin-1 , Ataxins , Behavior, Animal/physiology , Blotting, Western , Brain/anatomy & histology , Cerebellum/pathology , Chromatography, Gel , Female , Gene Expression , HEK293 Cells , Heredodegenerative Disorders, Nervous System/psychology , Humans , Immunoprecipitation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Phosphorylation , Protein Serine-Threonine Kinases , Spinocerebellar Ataxias/psychology
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