Huntingtin and Huntington's Disease


This site was created as a project for Genetics 677 at UW-Madison in the spring of 2009


Post-Translational Modifications


Phosphorylation sites

Phosphosite.org lists the various phosphorylation sites for the huntingtin protein.  The database lists 19 phosphorylation sites on the huntingtin protein, of which two are implicated through experimental in certain molecular processes.  Phosphorylation of serine 421 in huntingtin seems to be implicated in many of these processes, which includes cytoskeletal reorganization, regulation of apoptosis, activation, and regulation of molecular association.  The 421 site appears highly linked to the process of neurodegradation in Huntington's disease.  Regulation of phosphorlyation of the 421 site is regulated by Akt (PKB), described as a pro-surival signaling protein kinase, seems to have a protective function for huntingtin cleavage (1).  Researchers have noted that normal human and mice samples show a high level of phosphorylation of the 421 site through anti-body techniques, while Huntington's disease transgenic mouse models show decreased phosphoylation levels of the site in the striatum (1).  A more interested aspect of this study is the researchers demonstration that the levels of phosphorylation, in the mouse HD model, were higher in the cerebellum, slightly lower in in the cortex, and lowest in the striatum.  This seems to point to a regulatory interaction which may indicate why huntingtin is more destructive in the striatum than other brain cells.  Huntingtin is cleaved by apopain in a region from 400-490aa, so this phosporylation may be key in its abnormal cleavage and subsequent aggregation.  Other sites are also listed, but without the same level of association with Hungtington's disease. 

Above:  Image from Phosphosite.org of phosphorylation sites on the huntingtin protein. 

Above:  Reduced serine 421 phosphorylation in striatal cells (Warby et al. 2005).  Figure A demonstrates a reduction in the ratio of phosphorylated htt to unphosphorylated htt in striatal cells (St) compared to cortical (Cx) and cerebellar (Cb) cells in a Huntington's disease mouse model based upon an antibody specific to the site.  Figure B shows the activity of Akt, the kinase which phosphorylates huntingitn serine 421, based upon the ratio of activated (p-Akt) to inactivated (Akt) protein in the cell.  The activity of Akt is reduced in striatal cells based upon this result. 


1.  Warby, SC et al. 2005.  Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo.  Hum Mol Genet. 14(11) 1569-77.  doi:10.1093/hmg/ddi165

Created by Eric Nickels enickels@wisc.edu     4/23/2009      Genetics 677 Webpage