Metabolomic Nuclear Magnetic Resonance Studies at Presymptomatic and Symptomatic Stages of Huntington’s Disease on a Drosophila Model

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder, for which diagnostic development and discovery of new therapeutic targets are urgently required. In this study, a model of HD in Drosophila melanogaster has been used to identify metabolic biomarkers at presymptomatic and symptomatic stages of the disease. The pan-neuronal expression of a pathogenic fragment of the human Huntingtin (HTT) protein containing a 93-repeat polyglutamine expansion (Httex1p Q93) in transgenic flies induces a neuropathology with several characteristics of the human disease. The discriminant 2 metabolites between the diseased flies and their controls were identified by 1 H-nuclear magnetic resonance (NMR) and orthogonal partial least squares discriminant multivariate analysis (OPLS-DA). The experiments carried out with 10-day-old flies allowed us to identify a set of 10 biomarkers of the presymptomatic stage: NAD + , AMP, fumarate, asparagine, dimethylamine, -alanine, glutamine, succinate, glutamate and ethanol. Remarkably, the experiments conducted with 16-day-old flies, when the symptoms of the disease were present, highlighted a different set of 6 biomarkers: phosphocholine, ethanolamine, 2-oxoglutarate, succinate, pyruvate and acetate. Our results provide a better understanding of the metabolic impairments in a widely used HD model and demonstrate that metabolism perturbations change dramatically during the development of the disease.

Metabolic Alterations in a Drosophila Model of Parkinson’s Disease Based on DJ-1 Deficiency

“…To circumvent this limitation, we analyzed metabolites in the whole body of PD model flies. This experimental approach allows a complete panorama of PD-associated metabolic defects to be obtained, which are not restricted to the brain and can influence the physiology of the entire fly [33]. To date, only one similar study has been performed in another Drosophila PDf model based on PINK1 deficiency [64].…”

“…For instance, a metabolomic analysis of a Drosophila model of Charcot-Marie-Tooth disease based on GDAP1 deficiency allowed the involvement of insulin signaling in the characteristic neuromuscular degeneration of this disease to be identified [32]. Moreover, a transgenic Drosophila model of Huntington's disease was used to discover metabolic perturbations at two stages of the disease [33]. Regarding PD, Shukla et al [21] performed a metabolomic analysis in a paraquat-induced Drosophila model of iPD, in which altered levels of amino acids, lipids and carbohydrates were identified [21].…”

Metabolic alterations in a Drosophila model of Parkinson’s disease based on DJ-1 deficiency

“…To circumvent this limitation, we have analysed metabolites in the whole body of PD model flies. This experimental approach allows to obtain a complete panorama of PD-associated metabolic defects, which are not restricted to the brain and can influence the physiology of the entire fly [60]. To our knowledge, this is the first metabolomic analysis performed in a Drosophila model of fPD.…”

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.…”