The Urine Metabolome of R6/2 and zQ175DN Huntington’s Disease Mouse Models

Abstract

Huntington’s disease (HD) is caused by the expansion of a polyglutamine (polyQ)-encoding tract in exon 1 of the huntingtin gene to greater than 35 CAG repeats. It typically has a disease course lasting 15–20 years, and there are currently no disease-modifying therapies available. Thus, there is a need for faithful mouse models of HD to use in preclinical studies of disease mechanisms, target validation, and therapeutic compound testing. A large variety of mouse models of HD were generated, none of which fully recapitulate human disease, complicating the selection of appropriate models for preclinical studies. Here, we present the urinary liquid chromatography–high-resolution mass spectrometry analysis employed to identify metabolic alterations in transgenic R6/2 and zQ175DN knock-in mice. In R6/2 mice, the perturbation of the corticosterone metabolism and the accumulation of pyrraline, indicative of the development of insulin resistance and the impairment of pheromone excretion, were observed. Differently from R6/2, zQ175DN mice showed the accumulation of oxidative stress metabolites. Both genotypes showed alterations in the tryptophan metabolism. This approach aims to improve our understanding of the molecular mechanisms involved in HD neuropathology, facilitating the selection of appropriate mouse models for preclinical studies. It also aims to identify potential biomarkers specific to HD.

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“…Researchers have observed that restoring insulin signaling via SIRT2 inhibition provides neuronal protection ( Luthi-Carter et al, 2010 ; Arora and Dey, 2016 ). Additionally, liquid chromatography-high-resolution mass spectrometry analysis revealed insulin resistance in the urine of R6/2 mice ( Speziale et al, 2023 ). Transcriptomics investigations have also reported significant changes in several genes involved in glucose uptake and homeostasis ( Sorcs1 , Hh-II , and Vldlr ), with a lower glucose uptake rate in affected tissues and subsequent development of insulin resistance ( Chaves et al, 2017 ) ( Figure 2C ).…”