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. 2023 Aug 18;13(8):961.
doi: 10.3390/metabo13080961.

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

Roberto Speziale  1 , Camilla Montesano  2 , Giulia Di Pietro  3 , Daniel Oscar Cicero  3 , Vincenzo Summa  4 , Edith Monteagudo  5 , Laura Orsatti  1
Affiliations

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

Roberto Speziale et al. Metabolites. .

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.

Keywords: Huntington’s disease; R6/2 mice; mass spectrometry; urine metabolome; zQ175DN mice.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Workflow implemented to explore urine metabolic alteration in R6/2 and zQ175DN HD mice.
Figure 2
Figure 2
Workflow used for data analysis.
Figure 3
Figure 3
Template used for Compound Discoverer™ data analysis and the principal parameters used.
Figure 4
Figure 4
PCA score plot of the filtered dataset (RP and HILIC pos and neg) displaying the separation for R6/2 and wild-type 5- and 14–15-week-old mice. Tg mice at 14–15 weeks (green circle) showed separation from 5-week-old Tg (blue square), 5-week-old non-Tg (red triangle), and 14–15-week-old mice (azure square). One sample behaved as an outlier and was consequently excluded from the OPLS-DA analysis.
Figure 5
Figure 5
PCA score plot of the filtered dataset (RP and HILIC pos and neg) displaying moderate separation between zQ175DN groups by age and between zQ175DN mice at 15.7 months (blue square) and wild-type groups.
Figure 6
Figure 6
(A) OPLS-DA score plots displaying the separation for transgenic R6/2 (red square) and wild-type (blue triangle) 14–15-week-old mice. R2Y and Q2X were 0.99 and 0.97, respectively. (B) Permutation test showing the goodness of fit of the model built.
Figure 7
Figure 7
(A) OPLS-DA score plots display separation between 12- and 15.7-month-old zQ175DN mice (red circles) and 4-, 12-, and 15.7-month-old wild-type mice (blue squares). R2Y and Q2X were 0.94 and 0.78, respectively. Since only two samples were representing the knock-in mice at four months, they were excluded from the dataset. (B) Permutation test showing the goodness of fit of the model built.
Figure 8
Figure 8
S plot of (A) R6/2 versus wild-type mice and (B) zQ175DN versus wild-type mice.
See this image and copyright information in PMC

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