Ju et al. describe how hyperactivation of AMP-activated protein kinase (AMPK) promotes neurodegeneration in Huntington's disease (HD).
The aggregation of mutant Huntingtin protein in HD disrupts many cellular processes, including metabolism. AMPK—a protein that maintains energy homeostasis—is abnormally active in the brains of mice with HD, but whether the kinase protects neurons from the metabolic imbalances associated with HD or whether AMPK contributes to neuronal death is unknown.
Ju et al. determined that the α1 isoform of AMPK was specifically activated and translocated into the nuclei of neurons in a mouse model of HD, whereas AMPK-α2 was unaffected. An inhibitor of Ca2+/calmodulin-dependent protein kinase II reduced AMPK activity, suggesting that AMPK-α1 is activated by this kinase, probably because Ca2+ signaling is disrupted in HD neurons. Further stimulation of AMPK by injection of the AMPK-activating drug AICAR increased neuronal death and decreased the lifespan of HD mice. AICAR also promoted the death of neuronal cell lines, an effect reversed by an AMPK inhibitor. Active, nuclear AMPK-α1 promoted neuronal apoptosis by reducing expression of the survival factor Bcl2. Bcl2 levels and cell survival were restored by CGS21680, a drug that alleviates the symptoms of HD mice.
AMPK was also hyperactivated in the brains of human HD patients, suggesting that the kinase could be a therapeutic target. Senior author Yijuang Chern now wants to investigate how AMPK-α1 and -α2 isoforms are differentially regulated in neuronal tissue.