Research Article: Energy metabolism in ALS: an underappreciated opportunity?

Date Published: March 16, 2018

Publisher: Springer Berlin Heidelberg

Author(s): Tijs Vandoorne, Katrien De Bock, Ludo Van Den Bosch.


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.

Partial Text

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective and progressive degeneration of motor neurons in the brain and spinal cord. Motor neuron deterioration leads to muscle weakness and results in death due to respiratory failure typically within 3–5 years after diagnosis [25]. In the Western world, the lifetime risk of developing ALS is estimated to be 1 in 400 [89].

Control of whole-body energy homeostasis, the balance between energy uptake and expenditure, is crucial to maintain stable body weight and hence overall health [105]. In ALS patients, energy homeostasis is imbalanced [57]. While energy uptake is often lowered [1], energy expenditure is suggested to be increased in a significant proportion of patients with ALS [21]. While this observation stems from predictive equations which still need validation in ALS patients and should, therefore, be interpreted with care [176], energy expenditure exceeds uptake in most ALS patients, leading to reduced fat depots [81]. Imbalanced energy homeostasis is also a consistent finding in different SOD1 [56, 62] and TDP-43 mouse models [30, 36]. Recently, the melanocortin pathway, a critical regulator of energy homeostasis and food intake in the hypothalamus [184], was hypothesized to contribute to imbalanced energy homeostasis in ALS patients [67] and mice [201]. However, reducing energy expenditure and inducing hyperphagia by targeting this pathway in mutant SOD1G93A mice did not improve motor function or lifespan [53]. While the cause and importance of dysregulated energy homeostasis in human ALS remains to be established, body weight loss is an important prognostic factor in patients [149]. A lower pre-symptomatic body mass index has been reported in ALS patients [86, 126, 149] and the ALS risk is reduced up to 40% among obese individuals [138]. In agreement, increased prediagnostic body fat [65], subcutaneous fat [111], and serum leptin [135] were associated with a decreased risk of ALS mortality.

Since its first description by Charcot in 1869, the characteristic selective degeneration and death of motor neurons in ALS has remained an enigma. Neurons are large, polarized, excitable cells and, therefore, face unique challenges to maintain energy homeostasis (Fig. 1). They are the main contributors to the impressive energy demand of the central nervous system (CNS). First, action potential propagation is highly dependent on the Na+/K+-ATPase [75]. Second, due to the extensive length of their neurites, neurons, and, a fortiori, motor neurons, depend on axonal transport [155]. Importantly, the molecular motors driving axonal transport hydrolyze one ATP molecule, generated via on-board glycolysis [217], for every 8-nm displacement of their cargo [79, 167]. Since synapses are major sites of neuronal energy consumption, the trafficking of mitochondria is critical to meet synaptic energy requirements [174]. On top of this, high ATP concentrations are needed to keep proteins soluble [143]. The high dependence of motor neurons on continuous energy provision to maintain their normal function and integrity renders them particularly vulnerable to energetic stress [106].Fig. 1Overview 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

Energy metabolism is altered in ALS (Fig. 3) and correlates to disease progression, suggesting a role for energy metabolism in ALS pathogenesis. As a consequence, targeting metabolism represents a rational strategy to treat ALS. Below, we will give an overview of therapeutic approaches that target energy metabolism and have been tested in ALS patients and/or preclinical models (for an overview, see Table 1). Most approaches focus on increasing the provision of energetic substrates or improving mitochondrial function. Some strategies target the electron transport chain as the most important cellular source of oxidative stress. Creatine has also been investigated for its energy buffering capacities. Of note, most metabolic treatments have multiple mechanisms of action. One example is dichloroacetate, which improves mitochondrial function indirectly by stimulating the conversion of pyruvate to acetyl coenzyme A (ACoA), and, therefore, also provides additional energy substrates to the TCA cycle. For reasons of clarity, we classified treatments according to their principal mechanism of action.Table 1Metabolic treatments tested in ALSPutative mechanism of actionMetabolic treatmentEffect on ALS modelsEffect on ALS patientsEnergy buffering and transportCreatineImproved lifespan, motor neuron survival, and motor function in mutant SOD1G93A mice [87]No efficacy in phase II/III clinical trials [55, 139, 151]Oxidative stressCoenzyme Q10Improved survival in mutant SOD1G93A mice—[111]No efficacy in phase II clinical trial [81]MitoQReduced toxicity of mutant SOD1G93A rat astrocytes to healthy motor neurons in co-culture [24]Improved motor function, survival, and histopathology in mutant SOD1G93A mice [114]To be testedDexpramipexoleImproved survival, and motor function in mutant SOD1G93A mice in one study [36], but not in a second study [177]No effect in patient derived iPSCs [189]No effect in rat cortical neurons transfected with mutant or wild-type TDP-43 [177]No efficacy in phase III clinical trial [33]EdaravoneDelayed motor neuron degeneration and spinal cord SOD1 deposition in mutant SOD1G93A mice [71]Delayed disease progression in wobbler mice [69]Improved motor performance in mutant SOD1H46R rats [5]Efficacy in a subset of ALS patients [184], FDA-approvedAdditional and/or alternative fuelHigh caloric dietDelayed disease onset and extended survival in mutant SOD1G93A, mutant SOD1G86R, and mutant TDP-43A315T mice [30, 46]Delayed motor neuron loss in the spinal cord of mutant SOD1G93A mice [46]Promising results in a phase II clinical trial [182]Ketone bodiesKetogenic diets delay disease onset, improved motor neuron survival but not lifespan in mutant SOD1G93A mice [195]Ketone esters are to be tested in ALS modelsTo be testedMedium-chain triglyceridesDelayed disease onset, and improved motor neuron survival in mutant SOD1G93A mice [167, 193]To be testedPyruvateImproved motor performance, disease progression, and lifespan in mutant SOD1G93A mice [121] but not in a subsequent study [48]To be testedMitochondrial functionDichloroacetateImproved survival, delayed disease onset, and improved motor neuron survival in mutant SOD1G93A mice [113, 120]To be testedAcetyl-l-carnitineNeurotrophic effects in rat embryonic motor neurons [10]Improved survival in mutant SOD1G93A mice [86]Promising results in a phase II clinical trial [8]

While dysregulated systemic energy metabolism is now well established in ALS patients, energy metabolism has received a little attention in ALS research due to its association with mutant SOD1 models. It now becomes obvious that abnormal energy metabolism also has a role in more recently developed ALS models [118, 170, 183, 205]. In ALS motor neurons and glia, both mitochondrial and glycolytic energy metabolism seem to be impaired, but the molecular mechanisms underlying energetic stress remain unknown. Since motor neuron physiology is highly energy demanding, impairments in energy metabolism could, at least in part, explain the selective dying of motor neurons in ALS. As a consequence, targeting defects in energy metabolism in ALS represents a rational therapeutic strategy. Manipulating energy metabolism is a particularly potent strategy to treat complex diseases due to its intimate link to epigenetic control [60, 94, 119] and is, therefore, increasingly recognized as therapeutic target in cancer [28], immunodeficiency [123], and stroke [156]. To date, a unifying view on how different metabolic pathways converge and whether metabolic alterations contribute to disease etiology in ALS is non-existing. Future work using direct measurements of metabolic fluxes is clearly needed to obtain a more in-depth understanding of motor neuron metabolism in health and disease. Moreover, due to the compartmentalization of specific energy requiring processes in motor neurons, defining the role of metabolism and ALS-related motor neuron dysfunction requires high-resolution and spatial subdivision of metabolic and functional analyses. Knowing how ALS motor neurons differ metabolically from healthy motor neurons could offer the necessary insights to develop future therapeutic approaches in ALS. Another relevant area for future research is to explore the metabolic crosstalk between motor neurons and glial cells, as well as other disease-relevant cells such as the muscle.