Functional roles of the AMP‐activated protein kinase in Huntington's disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of CAG trinucleotide repeats in Huntingtin (Htt) gene. Accumulated evidence from different laboratories suggests the involvement of energy metabolism, excitotoxicity, and oxidative stress in HD pathogenesis. The common pathways linking Htt mutation with energy deficiency in HD remain largely unknown. We reported herein that a metabolic sensor (AMP‐activated protein kinase, AMPK) was overactivated in striatal cell lines (ST14A; STHdhQ7, STHdhQ109), as well as brains of a transgenic mouse model of HD (R6/2) and human HD patients. AMPK is a downstream mediator of many different types of stress. It composes a catalytic (α) and two regulatory subunits (β and γ), and can be activated by CaMKK and LKB1 via phosphorylation at the threonine residue 172 of AMPKα. In addition to suppressing metabolic enzymes (e.g., acetyl‐CoA carboxylase) and reducing ATP consumption upon stress, AMPK also phosphorylates a wide variety of proteins with different functions. We demonstrated in the present study that an agonist (CGS21680) of the A2A adenosine receptor (A2A receptor) not only produced beneficial effects on several major symptoms of HD in R6/2 mice, it also normalized the overactivated AMPK via a cAMP/protein kinase A‐ dependent pathway. Our findings shed new light on the metabolic aspects as well as the protective effects of cAMP‐elevating reagents in HD.