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Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity

Gaofeng Dong1, Kylie Gross, Fangfang Qiao

  • 1Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.

Journal of Neurochemistry
|August 16, 2012
PubMed

Insights

Calretinin (Cr) protein interacts with mutated huntingtin (mHtt) in Huntington's disease (HD). Overexpressing Cr reduces mHtt toxicity, suggesting Cr as a potential therapeutic target for HD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (Htt) gene.
  • Mechanisms of mutated Htt (mHtt) toxicity are not fully understood, necessitating new therapeutic targets.

Purpose of the Study:

  • To identify novel therapeutic targets for Huntington's disease.
  • To investigate the interaction between calretinin (Cr) and mutated huntingtin (mHtt).

Main Methods:

  • Tandem affinity purification to identify mHtt-associated proteins.
  • Coimmunoprecipitation and colocalization studies in neuronal cultures.
  • Cellular models of HD to assess the impact of Cr modulation.

Main Results:

  • Calretinin (Cr) preferentially associates with mutated huntingtin (mHtt) and also interacts with wild-type Htt.
  • Overexpression of Cr reduces mHtt-induced cytotoxicity in neuronal and non-neuronal cells.
  • Cr knockdown exacerbates mHtt-induced neuronal cell death.
  • Cr overexpression lowers intracellular free calcium and activates Akt.

Conclusions:

  • Calretinin (Cr) plays a protective role in Huntington's disease models.
  • Cr's interaction with mHtt and its effects on calcium levels and Akt signaling suggest it as a potential therapeutic target for HD.

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