Mutant Huntingtin(Htt) Activates AMPK-α1 in Mice Humans
Striatal neurons show AMP-activated protein kinase α1 activation in Huntington's disease
FRIDAY, July 22 (HealthDay News) -- The mutant huntingtin(Htt) (mHtt) gene activates the α1 isoform of adenosine mono phosphate (AMP)-activated protein kinase (AMPK-α1) in the striatal neurons of humans and mice with Huntington's disease (HD), and may be responsible for neuro-degeneration in the disease, according to an experimental study published online July 18 in the Journal of Cell Biology.
Tz-Chuen Ju, from the National Yang Ming University in Taiwan, and colleagues investigated whether activation of AMPK-α1 in striatal neurons is associated with mHtt-induced cell death in HD. Using an immunofluorescence staining technique, they evaluated the activation and subcellular localization of AMPK in the brains of patients with HD and in the striatum of a transgenic mouse model of HD. Experiments were performed to identify the entity in AMPK-α subunit that is regulated by the mHtt gene.
The investigators found that activation of the AMPK-α1 occurred in the striatal neurons of both humans and mice with HD. This nuclear accumulation of AMPK-α1 was dependent on activity. Over-activation of AMPKα1 in the mouse model resulted in brain atrophy, neuronal loss, and increased formation of Htt aggregates. Preventing nuclear translocation or AMPK-α1 inactivation reduced cell death and down-regulation of the Bcl2 gene caused by mHtt. The striatal cells were protected from the toxicity caused by mHtt and AMPK-α1 overactivation by enhanced Bcl2 expression.
"In this study, we demonstrated that mHtt activates AMPK-α1 and translocates it into the nuclei of two striatal cell lines that express mHtt and into nuclei of striatal neurons in mice and humans with HD," the authors write.