Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity

Gaofeng Dong, Kylie Gross, Fangfang Qiao, Justine Ferguson, Eduardo A. Callegari, Khosrow Rezvani, Dong Zhang, Christian J. Gloeckner, Marius Ueffing, Hongmin Wang

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expansion of CAG trinucleotide repeats encoding for polyglutamine (polyQ) in the huntingtin (Htt) gene. Despite considerable effort, the mechanisms underlying the toxicity of the mutated Htt protein remains largely uncertain. To identify novel therapeutic targets, we recently employed the approach of tandem affinity purification and discovered that calretinin (Cr), a member of the EF-hand family of calcium-binding proteins, is preferentially associated with mHtt, although it also interacts with wild-type Htt. These observations were supported by coimmunoprecipitation and by colocalization of Cr with mHtt in neuronal cultures. Over- expression of Cr reduced mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD, whereas knockdown of Cr expression in the cells enhanced mHtt-caused neuronal cell death. In addition, over-expression of Cr was also associated with reduction of intracellular free calcium and activation of Akt. These results suggest that Cr may be a potential therapeutic target for treatment of HD. Although previous studies have shown that calretinin (Cr), a calcium-binding protein, is associated with neuronal survival in Huntington's disease patients and in different models of the disease, direct physical and functional connections between Cr and mutant huntingtin (mHtt) are lacking. Here, we show that Cr interacts with mHtt and reduces mHtt-caused cytotoxicity in both non-neuronal and neuronal cell models of HD. These results suggest that Cr may be a potential therapeutic target for treatment of HD.

Original languageEnglish (US)
Pages (from-to)437-446
Number of pages10
JournalJournal of Neurochemistry
Volume123
Issue number3
DOIs
StatePublished - Nov 1 2012

Keywords

  • Huntington's disease
  • calcium-binding protein
  • calretinin
  • huntingtin
  • neuroprotection
  • polyglutamine

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Dong, G., Gross, K., Qiao, F., Ferguson, J., Callegari, E. A., Rezvani, K., Zhang, D., Gloeckner, C. J., Ueffing, M., & Wang, H. (2012). Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity. Journal of Neurochemistry, 123(3), 437-446. https://doi.org/10.1111/j.1471-4159.2012.07919.x