title: Metabolism in HD: still a relevant mechanism?
abstract: The polyglutamine expansion within huntingtin is the causative factor in the pathogenesis of Huntington's disease (HD). Although the underlying mechanisms by which mutant huntingtin causes neuronal dysfunction and degeneration have not been fully elucidated, compelling evidence suggests that mitochondrial dysfunction and compromised energy metabolism are key players in HD pathogenesis. Longitudinal studies of HD subjects have shown reductions in glucose utilization before the disease clinical onset. Preferential striatal neurodegeneration, a hallmark of HD pathogenesis, also has been associated with interrupted energy metabolism. Data from genetic HD models indicate that mutant huntingtin disrupts mitochondrial bioenergetics and prevents adenosine triphosphate (ATP) generation, implying altered energy metabolism as an important component of HD pathogenesis. Here we revisit the evidence of abnormal energy metabolism in the central nervous system of HD patients, review our current understanding of the molecular mechanisms underlying abnormal metabolism induced by mutant huntingtin, and discuss the promising therapeutic development by halting abnormal metabolism in HD.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000235:genetics*; D008659:Metabolic Diseases / Q000209:etiology / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D000255:Adenosine Triphosphate
keywords: AMPK; Huntington's disease; PGC-1α; energy metabolism; mitochondria; sirtuins