Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.

Amyotrophic Lateral Sclerosis and Occupational Exposures: A Systematic Literature Review and Meta-Analyses

“…Risk factors discussed are both physical trauma and chemicals. Confounders such as head trauma (in the case of Gulf veterans and professional athletes) and increased metabolism [103] caused by heavy physical work and agricultural work also might have an impact on the risk for ALS.…”

Adiponectin levels in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients: possible influence on neuroinflammation?

“…Several mechanisms contribute to altered energy balance in ALS from decreased energy supply and fat storage to increased energy expenditure (reviewed in [18]), but globally, these features appear to affect disease progression more than onset [18]. No influence of riluzole treatment on APN levels has been previously reported [32].…”

“…Interestingly, energy metabolism is impaired in both sporadic (sALS) and familiar ALS (fALS) patients [12, 17]. Hypermetabolism, weight loss, hyperlipidaemia and impaired glucose tolerance have been reported in ALS [17], although they are apparently related to advanced disease severity [18]. In fact, inclusions of TDP-43 (43-kDa trans-activation-responsive region DNA-binding protein) characterize most of ALS brain tissues whereas the naïve protein regulates fat deposition and glucose pathway [12, 19].…”

Impaired Bioenergetics in Clinical Medicine: A Target to Tackle

“…Impaired bioenergetics in the brain of HD and PD patients especially affects basal ganglia (Amano et al 2015) while energy deficit seems to commence in the precuneus and spread to other parts of the cerebral cortex in AD (Love and Miners 2016). In addition, a state of chronic energy deficit in the motor cortex has been reported in ALS (Ioannides et al 2016). Several recent reviews described possible therapeutic advances in targeting mitochondrial bioenergetics in neurodegeneration (Yao and Brinton 2011;Yadav et al 2014).…”