CNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target?

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.

Effect of Leptin Treatment in a Mouse Model of Tdp-43 Proteinopathy

“…Nevertheless, these correlations are not found in the TDP-43 A315T genotype, indicating a possible development of insulin resistance in this ALS model. On the other hand, a positive correlation was found between levels of GIP and PAI-1 as well as between GLP-1 and glucagon in TDP-43 A315T mice, in agreement with the metabolic impairments observed in ALS patients [39,40].…”

ILB® Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis

“…ALS has also been included in the list of chronic, progressive neurodegenerative disorders in which metabolic alterations, particularly those occurring to the so-called “central metabolism” [ 18 , 19 ], have been indicated not only as biochemical signatures of the disease [ 20 ] but also as molecular mechanisms connected to its pathogenesis and progression [ 21 , 22 ]. Hence, drug treatments capable of improving ALS-induced metabolic dysfunctions are considered as potentially promising therapies to be investigated in this still “orphan drug disease” [ 23 , 24 ]. Results reported in the present clinical trial strongly suggest that ILB ® administration produces metabolic benefits that are translated into evident improvements in clinical outcome for patients with ALS.…”

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

“…However, a substantial proportion of patients with ALS develop glucose intolerance [105,106]. Different preclinical studies also show problems affecting glucose transport and metabolism (recently reviewed by Tefera et al [107]), which imply progressive reductions in the capacity of MNs to generate energy from glucose, a metabolic problem that does not seem to affect, e.g., neighboring astrocytes, as shown in the SOD1 G93A ALS model [108]. In the event that the obtaining of energy from glucose progressively fails, it is obvious that MNs need an alternative source of energy to survive.…”