Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS.

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the SOD1G93A mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators.

34Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower 35 motor neurons, yet an increasing number of studies in both mouse models and patients with 36 ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical 37 studies have shown that modulation of energy balance can be beneficial in ALS. However, our 38 capacity to target specific metabolic pathways or mechanisms requires detailed understanding 39 of metabolic dysregulation in ALS. Here, using the SOD1 G93A mouse model of ALS, we 40 demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle 41 exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle 42 of ALS patients, we also show that increased dependence on fatty acid oxidation is associated 43 with increased whole-body energy expenditure. In the present study, increased fatty acid 44 oxidation was associated with slower disease progression. However, we observed considerable 45 heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. 46Thus, future studies that decipher specific metabolic changes at an individual patient level are 47 Indirect calorimetry 129Energy expenditure was measured with a Phenomaster open-circuit indirect calorimetry system 130 housed within a temperature (22°C) and 12h light, 12h dark cycle (on at 0600h and off at 1800h) 131 controlled chamber (TSE-Systems, Bad Homburg, DEU), as we have done previously (Steyn et 132 al., 2018c). Experimental cages (n=16) were sampled at 60min intervals for 3.5 min/cage, with 133 concentrations of O2 and CO2 in the outgoing air being measured sequentially within each 134 interval. One vacant cage was included to obtain a reference concentration for ambient gas. 135Activity (x-and y-plane), food intake, and body weight was recorded synchronously with 136 metabolic data. Measurements were performed continuously over 72h, with analysis restricted 137 to the final 24h assessment period (allowing 48h of acclimation). For data analysis, measures 138 of total energy expenditure and food intake were adjusted for body weight. 139 18 470The authors gratefully acknowledge the assistance and support of staff at the University of 471Queensland Biological Resources (UQBR), and The Centre for Integrated Physiology at the 472