Energy metabolism in ALS: an underappreciated opportunity?

Abstract

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder that primarily affects motor neurons. Despite our increased understanding of the genetic factors contributing to ALS, no effective treatment is available. A growing body of evidence shows disturbances in energy metabolism in ALS. Moreover, the remarkable vulnerability of motor neurons to ATP depletion has become increasingly clear. Here, we review metabolic alterations present in ALS patients and models, discuss the selective vulnerability of motor neurons to energetic stress, and provide an overview of tested and emerging metabolic approaches to treat ALS. We believe that a further understanding of the metabolic biology of ALS can lead to the identification of novel therapeutic targets.

Keywords: Amyotrophic lateral sclerosis; Energy metabolism; Metabolic dysfunction; Metabolic treatment; Mitochondria; Neuron-glia metabolic coupling.

Fig. 1

Overview of ATP consuming processes in motor neurons. Motor neuron physiology is highly energy demanding. First, the Na⁺/K⁺-ATPase and the Ca²⁺-ATPase hydrolyze ATP to establish and maintain the membrane potential and calcium homeostasis, respectively. Second, the molecular motors driving axonal transport depend on ATP hydrolysis. Third, synaptic activity is energetically expensive due to ion pumping, vesicular neurotransmitter uptake, and the endocytosis of vesicles from the synaptic cleft. Fourth, millimolar concentrations of ATP are required to maintain proteostasis. Gln glutamine, Glu glutamate, ATP adenosine triphosphate, ADP adenosine diphosphate, P inorganic phosphate

Fig. 2

Motor neuron metabolism in health. An overview of the current knowledge on motor neuron energy metabolism. Metabolic pathways are indicated in blue, important enzymes in red. Bold black arrows indicate the main metabolic routes in glia or motor neurons. Neurons have low glycogen stores and low expression and activity of PFKFB3. Activity of PDH is higher in neurons compared to glia. These differences result in a predominantly oxidative versus glycolytic metabolic profile in neurons and glia, respectively. According to the astrocyte-neuronal lactate shuttle hypothesis, glia-derived lactate is shunted to motor neurons where it undergoes oxidative phosphorylation. ROS generation in motor neurons promotes lipid production. These lipids are transported to glia where they can be stored or catabolized. Glut glucose transporter, HK hexokinase, G6P glucose 6-phosphate, R5P ribose 5-phosphate, F6P fructose 6-phosphate, PFK phosphofructokinase, PFKFB3 phosphofructokinase-2/fructose-2,6-bisphosphatase, F1,6BP fructose 1,6-bisphosphate, NADP+ oxidized nicotinamide adenine dinucleotide phosphate, NADPH reduced nicotinamide adenine dinucleotide phosphate, ROS reactive oxygen species, G3P glyceraldehyde 3-phosphate, LDH lactate dehydrogenase, PDH pyruvate dehydrogenase, Pdk4 pyruvate dehydrogenase kinase 4, Oxphos oxidative phosphorylation, MCT monocarboxylate transporter, ACoA acetyl coenzyme A, CPT1 carnitine palmitoyltransferase 1, TCA tricarboxylic acid cycle, O2 molecular oxygen, NADH reduced nicotinamide adenine dinucleotide, ETC electron transport chain, FATP fatty acid transport protein, APOE/D apolipoprotein E/D, ATP adenosine triphosphate, ADP adenosine diphosphate

Fig. 3

CNS energy metabolism is dysregulated in ALS. Metabolic processes shown to be affected in the CNS of ALS patients and/or models. Although most defects have not been attributed to a specific cell type, they are likely to result from either glia or motor neurons, or both. On the right, the presumably affected cell type(/s) is(/are) colored darker