Regulator of calcineurin (RCAN1-1L) is deficient in Huntington disease and protective against mutant huntingtin toxicity in vitro.
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).
Ermak
Gennady
G
Ethel Percy Andrus Gerontology Center and Division of Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089-0191, USA.
Hench
Karl J
KJ
Chang
Kevin T
KT
Sachdev
Sean
S
Davies
Kelvin J A
KJ
D000368:Aged; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D004268:DNA-Binding Proteins; C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C108612:RCAN1 protein, human; C097188:polyglutamine; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin