Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo

Simon C Warby, Edmond Y Chan, Martina Metzler, Lu Gan, Roshni R Singaraja, Susan F Crocker, Harold A Robertson, Michael R Hayden

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117 Citations (Scopus)


Huntington disease (HD) results from polyglutamine expansion in the huntingtin protein (htt). Despite the widespread tissue expression pattern of htt, neuronal loss is highly selective to medium spiny neurons of the striatum. Huntingtin is phosphorylated on serine-421 (S421) by the pro-survival signaling protein kinase Akt (PKB) and this has been previously shown to be protective against the toxicity of polyglutamine-expanded htt in cell culture. Using an antibody specific for htt phosphorylated on S421, we now demonstrate that htt phosphorylation is present at significant levels under normal physiological conditions in human and mouse brain. Furthermore, htt phosphorylation shows a regional distribution with the highest levels in the cerebellum, less in the cortex, and least in the striatum. In cell cultures and in YAC transgenic mice, the endogenous phosphorylation of polyglutamine-expanded htt is significantly reduced relative to wild-type htt. The presence and pattern of significant htt phosphorylation in the brain indicates that this dynamic post-translational modification is important for the regulation of htt and may contribute to the selective neurodegeneration seen in HD.

Original languageEnglish
Pages (from-to)1569-1577
Number of pages9
JournalHuman Molecular Genetics
Issue number11
Early online date20 Apr 2005
Publication statusPublished - 1 Jun 2005


  • amino acid sequence
  • base sequence
  • corpus striatum
  • DNA primers
  • humans
  • molecular sequence data
  • nerve tissue proteins
  • nuclear proteins
  • peptides
  • phosphorylation
  • sequence homology, amino acid
  • serine


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