Understanding and managing metabolic dysfunction in Amyotrophic Lateral Sclerosis

ABSTRACT

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease that leads to death after a median survival of 36 months. The development of an effective treatment has proven to be extremely difficult due to the inadequate understanding of the pathogenesis of ALS. Energy metabolism is thoroughly involved in the disease based on the discoveries of hypermetabolism, lipid/glucose metabolism, the tricarboxylic acid (TCA) cycle, and mitochondrial impairment.

Area covered

Many perturbed metabolites within these processes have been identified as promising therapeutic targets. However, the therapeutic strategies targeting these pathways have failed to produce clinically significant results. The authors present in this review the metabolic disturbances observed in ALS and the derived-therapeutics.

Expert opinion

The authors suggest that this is due to the insufficient knowledge of the relationship between the metabolic targets and the type of ALS of the patient, depending on genetic and environmental factors. We must improve our understanding of the pathological mechanisms and pay attention to the subtle hidden effects of changing diet, for example, and to use this strategy in addition to other drugs or to use metabolism status to determine subgroups of patients.

KEYWORDS:

• ALS
• metabolism
• metabolomics
• metabolic therapeutics
• TCA cycle
• metabolic alteration

Article highlights

• In regard to the successive unsuccessful clinical trials, the open-ended questions facing ALS researchers target personalized medicine.

• Many metabolic disturbances have been observed in ALS and derived-therapeutics are promising strategies.

• The different methods for metabolism exploration, including omics strategies have highlighted hypermetabolism, the alteration of metabolism of energetic substrates, tricarboxylic acid cycle dysfunction, electron transport chain alterations.

• These metabolic findings have supported the development of direct or indirect associated therapeutics such as supplementation in substrates, anaplerotic activation, the enzymatic activators.

• Unfortunately, the authors have noted a relative failure of metabolic therapeutics directly or indirectly targeting these pathways.

• The main limits of these kind of therapeutics are the timing and methodology used to treat ALS. They could be not suitable, mainly because they are based on different heterogenous reports of these metabolic disturbances published for many years.

• Side effects of some diet strategies must be taken into account, especially because some metabolic actors may totally unbalance metabolism

• The link metabolism-genetic status must be considered to better characterize ALS patients and to apply a more appropriate therapeutics strategy.

• The ways to pursue this metabolic strategy is to better understand the underlying mechanisms and to pay attention to the subtle hidden effects of changing diet for example, to use this strategy in addition to other drugs or to use metabolism status to determinate subgroups of patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.