NMR Spectroscopy-based Metabolomics of Drosophila Model of Huntington’s Disease Suggests Altered Cell Energetics

Abstract

Huntington's disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induces HD-like pathologies, progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated the 1D H NMR spectroscopy-based metabolomics profile of Drosophila HD model. Using multivariate analysis (PCA and PLS-DA) of metabolites obtained from methanolic extracts of fly heads displaying retinal deformations due to polyQ overexpression, we show that the metabolite imbalance during HD is likely to affect cell energetics. Six out of the 35 metabolites analyzed, namely, nicotinamide adenine dinucleotide (NAD), lactate, pyruvate, succinate, sarcosine, and acetoin, displayed segregation with progressive severity of HD. Specifically, HD progression was seen to be associated with reduction in NAD and increase in lactate-to-pyruvate ratio. Furthermore, comparative analysis of fly HD metabolome with those of mouse HD model and HD human patients revealed comparable metabolite imbalances, suggesting altered cellular energy homeostasis. These findings thus raise the possibility of therapeutic interventions for HD via modulation of cellular energetics.

NAD+ Metabolism and Diseases with Motor Dysfunction

“…In HD, changes in NAD + levels may reflect changes to cellular bioenergetics and may serve as a biomarker for disease progression [146][147][148]. Thus, NAD + metabolism has been investigated as an approach for treating HD symptoms.…”

Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications

“…From metabolomic studies, it has emerged that the metabolite (e.g., Trp, kynurenine, quinolinic acid and 3-hydroxykynurenine) content and activity of KP enzymes are pathologically altered in experimental HD models and human patients [109,110]. Moreover, in a Drosophila model of HD, disease progression has been found to be associated with a reduction in NAD levels, suggesting that dietetic or pharmacological supplementation of niacin (or its derivatives) may be useful in HD patients [157]. Several studies, indeed, have put forward a beneficial effect of vitamin B 3 in HD (Table 1): for example, nicotinamide is protective against toxicity of polyQ proteins in Drosophila HD models [158], while, in transgenic mouse models, it restores brain-derived neurotrophic factor (BDNF) protein levels, increases acetylated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, and improves motor deficits [159].…”

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

“…This observation is similar to the increased pyruvate/lactate ratio found in HD patients. Based on the above information, the imbalance in the NAD and lactate/pyruvate ratios are obvious perturbations in cellular energetics of HD fly tissues [113]. …”