Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421
Huntington's disease (HD) is caused by an abnormal expanded polyglutamine (polyQ) repeat in the huntingtin protein. Insulin-like growth factor-1 acting through the prosurvival kinase Akt mediates the phosphorylation of huntingtin at S421 and inhibits the toxicity of polyQ-expanded huntingtin in cell culture, suggesting that compounds enhancing phosphorylation are of therapeutic interest. However, it is not clear whether phosphorylation of S421 is crucial in vivo. Using a rat model of HD based on lentiviral-mediated expression of a polyQ-huntingtin fragment in the striatum, we demonstrate here that phosphorylation of S421 is neuroprotective in vivo. We next demonstrate that calcineurin (CaN), a calcium/calmodulin-regulated Ser/Thr protein phosphatase, dephosphorylates S421 in vitro and in cells. Inhibition of calcineurin activity, either by overexpression of the dominant-interfering form of CaN or by treatment with the specific inhibitor FK506, favors the phosphorylation of S421, restores the alteration in huntingtin S421 phosphorylation in HD neuronal cells, and prevents polyQ-mediated cell death of striatal neurons. Finally, we show that administration of FK506 to mice increases huntingtin S421 phosphorylation in brain. Collectively, these data highlight the importance of CaN in the modulation of S421 phosphorylation and suggest the potential use of CaN inhibition as a therapeutic approach to treat HD.
Keywords: Animals ; Brain/cytology/drug effects/enzymology ; Calcineurin/*antagonists & inhibitors/genetics ; Female ; Humans ; Huntington Disease/*enzymology/genetics ; Mice ; Mice ; Inbred C57BL ; Mutation ; Nerve Tissue Proteins/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Neurons/drug effects/enzymology ; Neuroprotective Agents/chemistry ; Nuclear Proteins/*antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Peptides/genetics/toxicity ; Phosphorylation ; Rats ; Rats ; Sprague-Dawley ; Rats ; Wistar ; Serine/metabolism ; Tacrolimus/*pharmacology ; Trinucleotide Repeat Expansion
Institut Curie, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 146, 91405 Orsay, France.
Record created on 2008-08-27, modified on 2016-08-08