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Carnosine (\u03b2-alanyl-L-histidine) has pathophysiological relevance due to its ability to detoxify reactive carbonyl species, including \u03b1,\u03b2-unsaturated aldehydes, scavenge free radicals, and chelate zinc, and has also been proposed to function in the central nervous system as a histidine reservoir for histamine synthesis. Here, we investigated the effects of carnosine supplementation on the cerebellar proteome of SOD1G93A ALS rats using quantitative proteomics. Carnosine treatment extensively remodeled mitochondrial, antioxidant, and synaptic vesicle-trafficking protein networks and increased the abundance of glutamatergic and GABAergic receptor subunits relative to untreated ALS animals, with several of these changes exceeding wild-type levels. Pathway enrichment analyses identified significant up-regulation of Rab-mediated vesicle trafficking, synaptic vesicle cycling, and neurotransmitter transport\/secretion pathways, alongside a partial reduction in RNA splicing and proteasomal subunits that were elevated in untreated ALS animals. Cross-comparison with the ALS-associated proteomic signature revealed that most carnosine-responsive proteins followed, rather than reversed, the direction of disease-associated change, indicating that carnosine predominantly potentiates an endogenous compensatory program rather than restoring a wild-type-like proteome. Collectively, these findings show that carnosine drives systems-level remodeling of mitochondrial and synaptic networks in the ALS cerebellum, identifying candidate compensatory pathways and supporting further functional validation of carnosine as a component of multimodal therapeutic strategies in ALS.<\/jats:p>","DOI":"10.3390\/antiox15091117","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:50:44Z","timestamp":1788529844000},"page":"1117","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Carnosine Potentiates a Compensatory Mitochondrial\u2013Synaptic Proteomic Response in the ALS Cerebellum"],"prefix":"10.3390","volume":"15","author":[{"given":"Hellen P.","family":"Valerio","sequence":"first","affiliation":[{"name":"GlycoProteomics Laboratory, Department of Parasitology, ICB, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0149-9707","authenticated-orcid":false,"given":"Valeria","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6921-2285","authenticated-orcid":false,"given":"Stephanie Y.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5921-0824","authenticated-orcid":false,"given":"Isabel R.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Palmisano","sequence":"additional","affiliation":[{"name":"GlycoProteomics Laboratory, Department of Parasitology, ICB, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mariana P.","family":"Massafera","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanderson S.","family":"Bispo","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4458-4354","authenticated-orcid":false,"given":"Fernanda M.","family":"Prado","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4125-8350","authenticated-orcid":false,"given":"Paolo","family":"Di Mascio","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5438-1174","authenticated-orcid":false,"given":"Marisa H. G.","family":"Medeiros","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica, Instituto de Qu\u00edmica, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: From genes to mechanism","volume":"539","author":"Taylor","year":"2016","journal-title":"Nature"},{"key":"ref_2","first-page":"181","article-title":"Risk factors for amyotrophic lateral sclerosis","volume":"7","author":"Ingre","year":"2015","journal-title":"Clin. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1097\/WCO.0000000000001294","article-title":"The genetics of amyotrophic lateral sclerosis","volume":"37","author":"Nijs","year":"2024","journal-title":"Curr. Opin. 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