Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease

Hum Mol Genet. 2015 Jan 1;24(1):86-99. doi: 10.1093/hmg/ddu456. Epub 2014 Sep 8.


Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology*
  • Brain / metabolism
  • Calcineurin / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism*
  • Phosphorylation
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • tau Proteins / metabolism*


  • Mapt protein, mouse
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • tau Proteins
  • Calcineurin