Metabolism in Huntington's disease: a major contributor to pathology

Abstract

Huntington's disease (HD) is a progressively debilitating neurodegenerative disease exhibiting autosomal-dominant inheritance. It is caused by an unstable expansion in the CAG repeat tract of HD gene, which transforms the disease-specific Huntingtin protein (HTT) to a mutant form (mHTT). The profound neuronal death in cortico-striatal circuits led to its identification and characterisation as a neurodegenerative disease. However, equally disturbing are the concomitant whole-body manifestations affecting nearly every organ of the diseased individuals, at varying extents. Altered central and peripheral metabolism of energy, proteins, nucleic acids, lipids and carbohydrates encompass the gross pathology of the disease. Intense fluctuation of body weight, glucose homeostasis and organ-specific subcellular abnormalities are being increasingly recognised in HD. Many of these metabolic abnormalities exist years before the neuropathological manifestations such as chorea, cognitive decline and behavioural abnormalities develop, and prove to be reliable predictors of the disease progression. In this review, we provide a consolidated overview of the central and peripheral metabolic abnormalities associated with HD, as evidenced from clinical and experimental studies. Additionally, we have discussed the potential of metabolic biomolecules to translate into efficient biomarkers for the disease onset as well as progression. Finally, we provide a brief outlook on the efficacy of existing therapies targeting metabolic remediation. While it is clear that components of altered metabolic pathways can mark many aspects of the disease, it is only conceivable that combinatorial therapies aiming for neuronal protection in consort with metabolic upliftment will prove to be more efficient than the existing symptomatic treatment options.

Keywords: Biomarker potential; Huntington’s disease; Metabolic dysfunction; Neurodegeneration; Peripheral tissues; Therapeutics.