Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motoneurons. While the principal cause of the disease remains so far unknown, the onset and progression of the pathology are increasingly associated with alterations in the control of cell metabolism. On the basis of the well-known key roles of 5'-adenosine monophosphate-activated protein kinase (AMPK) in sensing and regulating the intracellular energy status, we hypothesized that mice with a genetic deletion of AMPK would develop locomotor abnormalities that bear similarity with those detected in the very early disease stage of mice carrying the ALS-associated mutated gene hSOD1(G93A). Using an automated gait analysis system (CatWalk), we here show that hSOD1(G93A) mice and age-matched mice lacking the neuronal and skeletal muscle predominant α2 catalytic subunit of AMPK showed an altered gait, clearly different from wild type control mice. Double mutant mice lacking AMPK α2 and carrying hSOD1(G93A) showed the same early gait abnormalities as hSOD1(G93A) mice over an age span of 8 to 16 weeks. Taken together, these data support the concept that altered AMPK function and associated bioenergetic abnormalities could constitute an important component in the early pathogenesis of ALS. Therapeutic interventions acting on metabolic pathways could prove beneficial on early locomotor deficits, which are sensitively detectable in rodent models using the CatWalk system.

AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis

“…Inhibiting AMPK activity by raising cAMP levels also rescued TDP-43 mislocalisation in motor neuronal cells and delayed disease progression in TDP-43 WT mice [116]. Finally, AMPK a2 subunit gene ablation in mice was reported to induce gait disturbance that did not impact on motor symptoms in SOD1 G93A mice [64].…”

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

“…This viewpoint is supported by recent studies that investigated the consequences of the genetic ablation of AMPK, an enzyme that typically stimulates the consumption of fatty acids in skeletal muscle via the b-oxidation pathway. AMPK knockout mice exhibited gait disturbances reminiscent of that observed in the mutant SOD1 model (121). However, it should be taken into account that an enhanced oxidative metabolism, together with an excess of reactive oxygen species, would eventually lead to dysfunction of the respiratory electron transport chain, which would generate in itself more oxidative strees.…”

Constitutive downregulation protein kinase C epsilon in hSOD1G93A astrocytes influences mGluR5 signaling and the regulation of glutamate uptake

“…In this context, a critical role for PKCE has been demonstrated in the control neurites outgrowth (Chen & Tian, 2011;Shirai, Adachi, & Saito, 2008) and it has been reported that promoting axon regeneration could reduce the rate of skeletal muscle denervation and extend the life span of mice in a model of ALS (Jokic et al, 2006). The pathogenesis of ALS is also characterized by mitochondrial dysfunction and energy deficits (VandeVelde et al, 2011;Ioannides, Ngo, Henderson, Mccombe, & Steyn, 2016;Vergouts et al, 2015). Indeed, transplantation of neural precursors into the spinal cord of a mouse model of ALS gave rise to GFAP-positive donor cells that provided temporarily extended neuroprotection, improved motor function and prolonged animal survival times (Martin & Liu, 2007).…”

“…Indeed, transplantation of neural precursors into the spinal cord of a mouse model of ALS gave rise to GFAP-positive donor cells that provided temporarily extended neuroprotection, improved motor function and prolonged animal survival times (Martin & Liu, 2007). The pathogenesis of ALS is also characterized by mitochondrial dysfunction and energy deficits (VandeVelde et al, 2011;Ioannides, Ngo, Henderson, Mccombe, & Steyn, 2016;Vergouts et al, 2015). PKCd and PKCE participate in the control of cell energy homeostasis and an imbalance between these two PKCs is thought to disturb the flux of fuel entering the Krebs cycle and the overall production of energy (Gong et al, 2012).…”