{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T22:06:38Z","timestamp":1775253998504,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T00:00:00Z","timestamp":1692316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Huntington\u2019s 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\u201320 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\u2013high-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.<\/jats:p>","DOI":"10.3390\/metabo13080961","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:49:34Z","timestamp":1692582574000},"page":"961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Urine Metabolome of R6\/2 and zQ175DN Huntington\u2019s Disease Mouse Models"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7309-0703","authenticated-orcid":false,"given":"Roberto","family":"Speziale","sequence":"first","affiliation":[{"name":"Experimental Pharmacology Department, IRBM SpA, Via Pontina km 30.600, 00071 Pomezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-4961","authenticated-orcid":false,"given":"Camilla","family":"Montesano","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Di Pietro","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technology, University of Rome \u201cTor Vergata\u201d, Via Cracovia 50, 00133 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5012-1714","authenticated-orcid":false,"given":"Daniel Oscar","family":"Cicero","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences and Technology, University of Rome \u201cTor Vergata\u201d, Via Cracovia 50, 00133 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6288-2681","authenticated-orcid":false,"given":"Vincenzo","family":"Summa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Napoli \u201cFederico II\u201d, Corso Umberto I 40, 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2471-5695","authenticated-orcid":false,"given":"Edith","family":"Monteagudo","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5430-9965","authenticated-orcid":false,"given":"Laura","family":"Orsatti","sequence":"additional","affiliation":[{"name":"Experimental Pharmacology Department, IRBM SpA, Via Pontina km 30.600, 00071 Pomezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The biology of huntingtin","volume":"89","author":"Saudou","year":"2016","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: From molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_3","unstructured":"Bates, G.P., and Jones, L. (2002). Huntington\u2019s Disease, Oxford University Press."},{"key":"ref_4","first-page":"16","article-title":"Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats","volume":"59","author":"Rubinsztein","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"The Huntington\u2019s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. Cell, 72, 971\u2013983.","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s12035-012-8315-4","article-title":"Mouse models of polyglutamine diseases: Review and data table. Part I","volume":"46","author":"Figiel","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2008.06.005","article-title":"Rodent genetic models of Huntington disease","volume":"32","author":"Heng","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/nrn3570","article-title":"Choosing an animal model for the study of Huntington\u2019s disease","volume":"14","author":"Pouladi","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","article-title":"Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.nbd.2009.05.007","article-title":"Systematic behavioral evaluation of Huntington\u2019s disease transgenic and knock-in mouse models","volume":"35","author":"Menalled","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cmet.2011.02.013","article-title":"Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits","volume":"13","author":"Hult","year":"2011","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1093\/hmg\/ddl094","article-title":"Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6\/2 transgenic mouse model of Huntington\u2019s disease","volume":"15","author":"Petersen","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/jne.12190","article-title":"Hypothalamic Alterations in Huntington\u2019s Disease Patients: Comparison with Genetic Rodent Models","volume":"26","author":"Aziz","year":"2014","journal-title":"J. Neuroendocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.expneurol.2016.06.028","article-title":"Corticosterone dysregulation exacerbates disease progression in the R6\/2 transgenic mouse model of Huntington\u2019s disease","volume":"283 Pt A","author":"Dufour","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1093\/hmg\/ddw212","article-title":"An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes","volume":"25","author":"Southwell","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/mas.21455","article-title":"Mass spectrometric based approaches in urine metabolomics and biomarker discovery","volume":"36","author":"Khamis","year":"2017","journal-title":"Mass Spectrom. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1039\/C1AN15605E","article-title":"Modern analytical techniques in metabolomics analysis","volume":"137","author":"Zhang","year":"2012","journal-title":"Analyst"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cca.2012.08.016","article-title":"Urine metabolomics","volume":"414","author":"Zhang","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Petrella, G., Montesano, C., Lentini, S., Ciufolini, G., Vanni, D., Speziale, R., Salonia, A., Montorsi, F., Summa, V., and Vago, R. (2021). Personalized metabolic profile by synergic use of NMR and HRMS. Molecules, 26.","DOI":"10.21203\/rs.3.rs-442781\/v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D603","DOI":"10.1093\/nar\/gkn810","article-title":"HMDB: A knowledgebase for the human metabolome","volume":"37","author":"Wishart","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/nar\/27.1.29","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"27","author":"Ogata","year":"1999","journal-title":"Nucleic Acids Res."},{"key":"ref_22","first-page":"258","article-title":"Molecular formula and METLIN Personal Metabolite Database matching applied to the identification of compounds generated by LC\/TOF-MS","volume":"19","author":"Sana","year":"2008","journal-title":"J. Biomol. Tech."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.aca.2016.12.029","article-title":"Metabolomic analysis of urine samples by UHPLC-QTOF-MS: Impact of normalization strategies","volume":"955","author":"Gagnebin","year":"2017","journal-title":"Anal. Chim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10925","DOI":"10.1021\/ac503190m","article-title":"Normalization to specific gravity prior to analysis improves information recovery from high-resolution mass spectrometry metabolomic profiles of human urine","volume":"86","author":"Edmands","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6061","DOI":"10.1021\/ac900333e","article-title":"Integrated comparison of drug-related and drug-induced ultra-performance liquid chromatography\/mass spectrometry metabonomic profiles using human hepatocyte cultures","volume":"81","author":"Croixmarie","year":"2009","journal-title":"Anal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.4155\/bio.09.146","article-title":"Simple data-reduction method for high-resolution LC-MS data in metabolomics","volume":"1","author":"Scheltema","year":"2009","journal-title":"Bioanalysis"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Saleh, N., Moutereau, S., Durr, A., Krystkowiak, P., Azulay, J.-P., Tranchant, C., Broussolle, E., Morin, F., Bachoud-L\u00e9vi, A.-C., and Maison, P. (2009). Neuroendocrine Disturbances in Huntington\u2019s Disease. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004962"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1006\/abbi.1996.0019","article-title":"Pyrraline ether crosslinks as a basis for protein crosslinking by the advanced Maillard reaction in aging and diabetes","volume":"325","author":"Nagaraj","year":"1996","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1196\/annals.1433.016","article-title":"Evaluating the extent of protein damage in dairy products","volume":"1126","author":"Hegele","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1093\/hmg\/ddi053","article-title":"The R6\/2 transgenic mouse model of Huntington\u2019s disease develops diabetes due to deficient beta-cell mass and exocytosis","volume":"14","author":"Fex","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5710","DOI":"10.1073\/pnas.91.12.5710","article-title":"Advanced Maillard reaction end products are associated with Alzheimer disease pathology","volume":"91","author":"Smith","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1042\/BJ20050404","article-title":"Structural and functional differences in isoforms of mouse major urinary proteins: A male-specific protein that preferentially binds a male pheromone","volume":"391","author":"Armstrong","year":"2005","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"R\u00f6ck, F., Hadeler, K.-P., Rammensee, H.-G., and Overath, P. (2007). Quantitative analysis of mouse urine volatiles: In search of MHC-dependent differences. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0000429"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1021\/bi00686a033","article-title":"Isolation and identification of L-\/3-aspartyl-L-lysine and L-y-glutamyl-L-ornithine from normal human urine","volume":"14","author":"Lou","year":"1975","journal-title":"Biochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s00216-002-1634-y","article-title":"Voltammetric determination of thiodiglycolic acid in urine","volume":"375","year":"2003","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_36","unstructured":"Fanjul-Moles, M.L. (2008). Comparative Aspects of Circadian Rhythms, Rans World Research Network."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/8\/961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:37:15Z","timestamp":1760128635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/8\/961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,18]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["metabo13080961"],"URL":"https:\/\/doi.org\/10.3390\/metabo13080961","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,18]]}}}