Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro

Gennady Ermak, Karl J. Hench, Kevin T. Chang, Sean Sachdev, Kelvin J A Davies

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Our work suggests an important new link between the RCAN1 gene and Huntington disease. Huntington disease is caused by expansion of glutamine repeats in the huntingtin protein. How the huntingtin protein with expanded polyglutamines (mutant huntingtin) causes the disease is still unclear, but phosphorylation of huntingtin appears to be protective. Increased huntingtin phosphorylation can be produced either by inhibition of the phosphatase calcineurin or by activation of the Akt kinase. The RCAN1 gene encodes regulators of calcineurin, and we now demonstrate, for the first time, that RCAN1-1L is depressed in Huntington disease. We also show that RCAN1-1L overexpression can protect against mutant huntingtin toxicity in an ST14A cell culture model of Huntington disease and that increased phosphorylation of huntingtin via calcineurin inhibition, rather than via Akt induction or activation, is the likely mechanism by which RCAN1-1L may be protective against mutant huntingtin. These findings suggest that RCAN1-1L "deficiency" may actually play a role in the etiology of Huntington disease. In addition, our results allow for the possibility that controlled overexpression of RCAN1-1L in the striatal region of the brain might be a viable avenue for therapeutic intervention in Huntington disease patients (and perhaps other polyglutamine expansion disorders).

Original languageEnglish (US)
Pages (from-to)11845-11853
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number18
DOIs
StatePublished - May 1 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro'. Together they form a unique fingerprint.

Cite this