Polyglutamine disease toxicity is regulated by nemo-like kinase in spinocerebellar ataxia type 1

Hyoungseok Ju, Hiroshi Kokubu, Tiffany W. Todd, Juliette J. Kahle, Soeun Kim, Ronald Richman, Karthik Chirala, Harry T. Orr, Huda Y. Zoghbi, Janghoo Lim

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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 reducingNLKenzymatic activity or decreasingNLKexpression levels can have beneficial effects against the toxicity induced by polyglutamine-expanded ATXN1.

Original languageEnglish (US)
Pages (from-to)9328-9336
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number22
DOIs
StatePublished - May 29 2013

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Spinocerebellar Ataxias
Phosphotransferases
Phenotype
Trinucleotide Repeats
Protein-Serine-Threonine Kinases
Glutamine
Neurodegenerative Diseases
Drosophila
polyglutamine
Proteins
Pathology

Cite this

Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., ... Lim, J. (2013). Polyglutamine disease toxicity is regulated by nemo-like kinase in spinocerebellar ataxia type 1. Journal of Neuroscience, 33(22), 9328-9336. https://doi.org/10.1523/JNEUROSCI.3465-12.2013

Polyglutamine disease toxicity is regulated by nemo-like kinase in spinocerebellar ataxia type 1. / Ju, Hyoungseok; Kokubu, Hiroshi; Todd, Tiffany W.; Kahle, Juliette J.; Kim, Soeun; Richman, Ronald; Chirala, Karthik; Orr, Harry T.; Zoghbi, Huda Y.; Lim, Janghoo.

In: Journal of Neuroscience, Vol. 33, No. 22, 29.05.2013, p. 9328-9336.

Research output: Contribution to journalArticle

Ju, H, Kokubu, H, Todd, TW, Kahle, JJ, Kim, S, Richman, R, Chirala, K, Orr, HT, Zoghbi, HY & Lim, J 2013, 'Polyglutamine disease toxicity is regulated by nemo-like kinase in spinocerebellar ataxia type 1', Journal of Neuroscience, vol. 33, no. 22, pp. 9328-9336. https://doi.org/10.1523/JNEUROSCI.3465-12.2013
Ju, Hyoungseok ; Kokubu, Hiroshi ; Todd, Tiffany W. ; Kahle, Juliette J. ; Kim, Soeun ; Richman, Ronald ; Chirala, Karthik ; Orr, Harry T. ; Zoghbi, Huda Y. ; Lim, Janghoo. / Polyglutamine disease toxicity is regulated by nemo-like kinase in spinocerebellar ataxia type 1. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 22. pp. 9328-9336.
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