Towards an Understanding of Energy Impairment in Huntington’s Disease Brain

Abstract

This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington’s disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection. As a result, oxidative damage to key glycolytic and tricarboxylic acid (TCA) cycle enzymes further restricts energy production so that while basal needs may be met through oxidative phosphorylation, those of excessive stimulation cannot. Energy production may also be compromised by deficits in mitochondrial biogenesis, dynamics or trafficking. Restrictions on energy production may be compensated for by glutamate oxidation and/or stimulation of fatty acid oxidation. Transcriptional dysregulation generated by mutant huntingtin also contributes to energetic disruption at specific enzymatic steps. Many of the alterations in metabolic substrates and enzymes may derive from normal regulatory feedback mechanisms and appear oscillatory. Fine temporal sequencing of the shifts in metabolic flux and transcriptional and expression changes associated with mutant huntingtin expression remain largely unexplored and may be model dependent. Differences in disease progression among HD model systems at the time of experimentation and their varying states of metabolic compensation may explain conflicting reports in the literature. Progressive shifts in metabolic flux represent homeostatic compensatory mechanisms that maintain the model organism through presymptomatic and symptomatic stages.

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

“…Like the Q175 mutants, the R6/2 mice also exhibited episodes of hypothermia, particularly evident in the dark period. Overall, there is strong evidence for mitochondrial dysfunction in HD as well as in other neurodegenerative diseases (Carmo, Naia, Lopes, & Rego, ; Dubinsky, ; Franco‐Iborra, Vila, & Perier, ; Kuhl et al, ; Naseri et al, ). Unintended weight loss is a hallmark of HD patients and a recent study found that a high body mass index (BMI) is associated with a significantly slower rate of functional, motor, and cognitive deterioration (van der Burg et al, ).…”

Complementarity of gluCEST and 1H‐MRS for the study of mouse models of Huntington's disease

“…In addition, Glu can also be implicated in energy production through its equilibrium with alpha‐ketoglutarate, an intermediate of the Krebs cycle. One can hypothesize that dynamic adaptations of metabolic fluxes may take place during the animal's lifespan in order to counterbalance disturbance of homeostasis and energy production due to mutant huntingtin 39 . One can assume that such compensatory mechanisms would be more efficient in slowly progressive models than in severe forms, where the aggravations of alterations of brain cells are probably faster and might not be counterbalanced.…”

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

“…For example, HD patients show excessive weight loss despite normal food intake [165]. Glucose metabolism is decreased in affected brain regions of HD patients, and post-mortem brain samples exhibit decreased mitochondrial respiratory complex activity [166,167]. Moreover, mitochondrial malfunction occurs not only in affected brain regions but also in peripheral tissues such as skin fibroblasts derived from HD patients [168].…”