We searched Medline for articles published between January, 1960, and September, 2010, with the search terms “amyotrophic lateral sclerosis” and “motor neuron disease”, in combination with “metabolism”, “energy expenditure”, “lipids”, “diabetes”, “mitochondria”, “ApoE” or “cholesterol”. Only full-text reports written in English or French were selected. We also used articles from our own files and databases when appropriate.
ReviewEnergy metabolism in amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is characterised by the simultaneous degeneration of lower (spinal and bulbar) and upper (corticospinal) motor neurons, leading to progressive muscle atrophy and paralysis.1 Motor neuron degeneration is mostly associated with pathological aggregation of ubiquitin, the fused in sarcoma protein (FUS), and the TAR DNA binding protein of 43-kDa TDP-43 (TDP-43) in the cytoplasm of motor neuron cell bodies.2, 3 ALS generally leads to death within 2–3 years of diagnosis, mostly from respiratory failure.4, 5 The incidence of this disorder (1·5–3·0 per 100 000) is similar to that of multiple sclerosis, but the prevalence of ALS is much lower owing to the poor prognosis. Clinical presentation is heterogeneous, which suggests that ALS is a syndrome rather than one nosological entity.5 In support of this theory, various seemingly unrelated causes of ALS have been described, including toxic6, 7 and genetic8 causes. Most ALS cases (90%), however, are of unknown origin, with no obvious family history, and are termed sporadic ALS. No firmly replicated genetic risk factor for sporadic ALS has emerged from genome-wide association studies, except the association with a narrow region on chromosome 9p21.9, 10 ALS is sometimes associated with non-motor symptoms, most notably with frontotemporal dementia,11 and the occurrence of TDP-43-positive aggregates in patients with ALS, frontotemporal dementia, or both, strongly supports the existence of a pathophysiological continuum between these two disorders.12
Initially, pathological abnormalities in ALS were thought to be restricted to motor neurons, but descriptions of a wider dissemination of effects throughout the body have challenged this classic paradigm. Several lines of investigation have clearly demonstrated that ALS is a systemic disease, including presentations of diffuse brain involvement. Further extending this notion, ALS disease seems to be restricted not only to the CNS but also affects whole-body physiology. In particular, energy metabolism is severely altered in patients with ALS, which has notable clinical implications. In this Review, we focus on the alterations of energy homoeostasis in ALS, how they contribute to the overall pathogenic process, and how they might constitute targets for new therapeutic strategies.
Section snippets
Impairment of energy metabolism
Energy homoeostasis results from the balance of energy intake and energy expenditure. In healthy people, food intake and nutrient absorption are theoretically in balance with basal (resting) and activity-induced energy expenditure (figure 1). This balance in healthy adults leads to roughly stable energy stores, mostly in the form of triglycerides in adipocytes, and hence to a stable body-mass index. Energy homoeostasis requires that uptake of nutrients in cells, including glucose and lipids, is
Energy metabolism and prognosis
The occurrence of defective energy metabolism in patients with ALS is not necessarily pathogenic or related to disease status. Several correlative studies have, however, provided some indication of a pathogenic role. First, weight loss and malnutrition are negatively associated with survival and are important prognostic factors in ALS.15, 37, 38, 39 By contrast, hyperlipidaemia23 and increased concentrations of circulating apolipoprotein E24 are positively correlated with survival in ALS, which
Energy metabolism and motor neuron degeneration
As study of the presymptomatic and early phases of ALS is very difficult in people, animal models are crucial to research. Since the discovery of mutations in the SOD1 gene linked to familial ALS,8 several transgenic mouse and rat models overexpressing various mutant isoforms have been developed that produce good representations of the cardinal symptoms of ALS in human beings.46 In transgenic mice expressing human mutant SOD1, upper and lower motor neurons degenerate,47 and tremor, paralysis,
Modification of energy metabolism
Most, if not all, potential environmental modifiers known or postulated to modulate the ALS disease course affect energy metabolism. The four main potential areas of interest in ALS are neurotoxins, exercise, response to hypoxia, and statin treatment (panel). We discuss these features below in the context of ALS, but also in the context of other motor neuron diseases when relevant information is available.
Consequences for nutritional management
The importance of nutritional management in ALS has been stressed in the guidelines of the American Academy of Neurology87 and the European Federation of Neurological Societies.88 Initial management consists of dietary counselling, modification of consistency in the types of food eaten, and prescription of high-calorie supplements. No consensus has been reached on the timing of tube feeding, and decisions are currently based on presence of dysphagia, nutritional status, and respiratory function.
Conclusions
Clinical and experimental studies have shown indisputably that abnormal energy homoeostasis has a role in ALS, and that therapeutic strategies should be aimed at correcting defective energy metabolism, but definitive data are scarce. Research in ALS should be directed by findings in other disorders. For instance, the incidence of diabetes is higher among patients with Huntington's disease97 and Alzheimer's disease98 than in the general population, and high-fat feeding in mouse models of the
Search strategy and selection criteria
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