AMP-activated protein kinase (AMPK) in neurodegeneration
AMPK regulates energy balance at both the cellular and whole-body levels. It is switched on in response to metabolic stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off energy-consuming anabolic processes.
Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology, including neurodegeneration. Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, ALS, prion diseases and polyglutamine disorders, including Huntington’s disease are associated with the formation of protein aggregates. These aggregates and/or their precursors are thought to be toxic disease-causing species. Autophagy is a major degradation pathway for intracytosolic aggregate-prone proteins, including those associated with neurodegeneration. In cell and animal models, induction of autophagy protects against the toxic insults of these mutant aggregate-prone proteins by enhancing their clearance. Autophagy promotes energy generation and activation of AMPK induces autophagy by inhibiting mammalian target of rapamycin (mTOR) signaling which suppresses autophagy. Thus, AMPK activators may be developed to prevent or treat neurodegenerative disorders.
Betagenon AB has developed novel direct AMPK activators, and we are in collaboration with Betagenon AB elucidating the role of AMPK activation in neurodegenerative disorders.