Metabolic-based therapeutic strategies to treat Huntington's disease.

Huntington's disease is an autosomal dominant neurodegenerative disorder marked by progressive motor, cognitive, and psychiatric decline. Huntington's disease arises from the expansion of particular DNA sequences (cytosine/ adenosine/guanine repeats that encode glutamine) within the huntingtin (HTT) gene. This expansion leads to the synthesis of a mutant huntingtin protein (mhtt) featuring an excessively long polyglutamine segment, which is harmful and prone to form aggregates or clusters within cells. A range of abnormalities has been observed in both the central nervous system and peripheral tissues as a consequence of mhtt. These include inhibition in autophagy, mitochondrial dysfunction leading to metabolic deficiencies, immune system dysregulation, metabolic alterations, skeletal muscle deterioration, heart failure, testicular shrinkage, and bone density loss. Additionally, mhtt has been implicated in altering lipid metabolism pathways, leading to an increase in lipid accumulation, especially within neuronal cells. This lipid accumulation contributes significantly to cellular toxicity and dysfunction, further exacerbating the neurodegeneration seen in Huntington's disease. Although most studies have focused on neurological, behavioral, motor, and cognitive changes associated with Huntington's disease, several studies have reported changes in proteins, nucleic acids, lipids, and carbohydrate metabolism, which may lead to an anomalous molecular energy profile in individuals with Huntington's disease. This review will focus on understanding how metabolic changes may contribute to central alterations in Huntington's disease by analyzing preclinical and clinical evidence. Additionally, it will explore potential pathways that could be targeted to develop more effective treatments for Huntington's disease.