Centrally and peripherally altered glucose transporters: is it time to revisit energy deficiency as a potential treatment strategy in Huntington's disease?

Huntington's disease is classically looked upon solely as a genetic neurodegenerative disease. However, the disease is a whole-body disorder and presents not only with neuronal pathology, but with wide-spread pathological alterations.^1,2 The increased CAG repeat number in the gene coding for the protein huntingtin is expressed throughout the body and peripheral pathology has been suggested to parallel central events. Indeed, weight loss, endocrine alterations, and muscle pathology are a few of the peripheral manifestations that are present in Huntington's disease.² Paediatric or juvenile-onset Huntington's disease refers to approximately 5% of patients with symptom onset before the age of 21.³ These patients present with a more severe pathology and disease progression.³ Intriguingly, glucose transporter (GLUT)-1 deficiency syndrome, resulting in impaired passive glucose transport across the blood–brain barrier, presents with complex motor dysfunction, such as dystonia, ataxia, chorea, and spasticity.⁴ Interestingly, these features are reminiscent of juvenile Huntington's disease features.

Today, we still do not have the full picture of the relationship between glucose transporters, glucose metabolism and neurodegeneration, but the work of Tramutola and colleagues published in the November issue of eBioMedicine provides ideas for further research. The authors demonstrate that glucose transporters, GLUT-1 (across the blood–brain barrier) and GLUT-3 (across neuronal membranes) could be deficient in paediatric Huntington's disease, both centrally and peripherally. In addition, results suggest that the mitochondrial machinery involved in glucose metabolism is deregulated in these patients. Despite the small sample size, this study points to the potential importance of altered glucose transporters in the brain and periphery of paediatric Huntington's disease patients and illustrates the potential of utilizing peripheral cells and tissue as models to investigate Huntington's disease relevant biological signatures.

Alterations in proteins, nucleic acids, lipids, and carbohydrate metabolism have been described and an abnormal molecular energy metabolic signature has been shown in tissue samples from patients with Huntington's disease.⁵ The concept of Huntington's disease as a potential metabolic disorder was launched already in 1972, when Podolsky and colleagues presented evidence for an increased frequency of diabetes among patients with Huntington's disease.⁶ Central glucose metabolism, illustrated by decreased striatal glucose metabolism, has been showed to be altered in Huntington's disease and increasing evidence supports that neuronal glucose uptake is impaired.⁷ The altered glucose uptake by the brain and neurons is an important component of central glucose hypometabolism in Huntington's disease patients.

There is a need to understand energy metabolism dysfunction in Huntington's disease, both at whole body and cellular level. Even though Tramutola and colleagues present a study limited to two patients with paediatric Huntington's disease,⁸ the study highlights the potential of juvenile Huntington's disease as a source of knowledge that can guide future studies relevant for adult Huntington's disease as well. The metabolic alterations found in Huntington's disease are subtle and progress slowly, contributing to the difficulties to pin-point metabolic dysfunction. Juvenile Huntington's disease cases, by providing insight into a more severe disease state, could guide research and suggest metabolic pathways of interest for further investigation.

Metabolism involves multiple cells and organs throughout the body. Metabolic pathways provide a complex network, and metabolic dysregulation linked to the huntingtin mutation and associated compensatory mechanisms adds to the challenges. Cells and tissue have different capacities to compensate dysfunction, and central and peripheral neuronal cell populations affected by Huntington's disease are possibly more vulnerable. Further illustrating the complexity and emphasizing the importance of choosing the right parameters to investigate dysfunction, a decreased striatal glucose metabolism has been demonstrated in patients with Huntington's disease but affects symptom presentation only when it falls below a certain threshold.⁷ Despite the challenges and the incomplete picture of how energy deficit is related to neurodegeneration, molecular and biochemical evidence suggest the potential of targeting energy deficit in Huntington's disease.

Strategies to overcome energy deficiency indeed show promise. Ketones can be utilized by neurons as an energy source more efficient than glucose, resulting in beneficial metabolic changes, and high-fat, low-carbohydrate diets, known as ketogenic diets, have been suggested to prevent neurodegeneration in Alzheimer's disease and to normalize insulin resistance in type 2 diabetes.⁹ Strategies to overcome energy deficit in human Huntington's disease have also yielded promising results. Dietary anaplerotic therapy, by providing substrates to the Krebs cycle, has been shown to improve peripheral tissue energy metabolism and to correct the bioenergetic profile in the brain of patients with Huntington's disease at an early stage of the disease.¹⁰

Studies focusing on the low-grade metabolic alterations found in Huntington's disease are needed. Possibly, the rare cases of juvenile Huntington's disease can yield important knowledge on the complexity of Huntington's disease related metabolic changes. An increased understanding of the underlying causes has the potential to guide future therapeutic strategies to normalize whole body energy metabolism and maintain intracellular cellular energy metabolism.

Contributors

MB is the sole author.

Declaration of interests

No conflict of interest.