{"doi":"10.3390/ijms25137149","title":"Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain—Study in a Mouse Model of the Disease","abstract":"<jats:p>Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p &lt; 0.0001), and in the bran, decreased 8-isoprostane amounts (p &lt; 0.0001), increased resolvin D1 levels (p &lt; 0.005) and increased quantity of total n-3 PUFAs (p &lt; 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = −0.562, p = 0.0001), resolvin D1 (r = 0.712, p &lt; 0.0001), and 8-isoprostane brain levels (r = −0.690, p &lt; 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.</jats:p>","journal":"International Journal of Molecular Sciences","year":2024,"id":636010,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1650320,"name":"Giovanna Pannuzzo","orcid":null,"position":1,"is_corresponding":false},{"id":1650321,"name":"Adriana Carol Eleonora Graziano","orcid":null,"position":2,"is_corresponding":false},{"id":1650322,"name":"Elena Moretti","orcid":"0000-0002-9467-0501","position":3,"is_corresponding":false},{"id":1650324,"name":"Giulia Collodel","orcid":"0000-0003-1587-0159","position":4,"is_corresponding":false},{"id":1650325,"name":"Venera Cardile","orcid":null,"position":5,"is_corresponding":false},{"id":1650319,"name":"Cinzia Signorini","orcid":"0000-0003-0006-9414","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain—Study in a Mouse Model of the Disease","abstract":"<jats:p>Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p &lt; 0.0001), and in the bran, decreased 8-isoprostane amounts (p &lt; 0.0001), increased resolvin D1 levels (p &lt; 0.005) and increased quantity of total n-3 PUFAs (p &lt; 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = −0.562, p = 0.0001), resolvin D1 (r = 0.712, p &lt; 0.0001), and 8-isoprostane brain levels (r = −0.690, p &lt; 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.</jats:p>","is_dataset_classified":null,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39000257","pmcid":"PMC11241235","openalex_id":"https://openalex.org/W4400235809","authors":[],"funders":[{"funder_name":"Italian Association for Leucodistrophy of Krabbe “Progetto Grazia”","grant_id":"20821141006/55048726","title":null}],"total_grants":1,"fwci":0.7346,"citation_percentile":0.70042565,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/25/13/7149/pdf?version=1720401019","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/25/13/7149/pdf?version=1720401019","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/25/13/7149/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms25137149","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39000257","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11241235","host_type":"repository"},{"url":"https://www.mdpi.com/1422-0067/25/13/7149","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11241235/pdf/ijms-25-07149.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11241235","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11241235?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Lysosomal Storage Disorders Research","Trypanosoma species research and implications","Carbohydrate Chemistry and Synthesis","Animals","Dietary Supplements","Mice","Fatty Acids, Omega-3","Disease Models, Animal","Brain","Leukodystrophy, Globoid Cell","Phenotype","Docosahexaenoic Acids","Lipid Metabolism","Dinoprost","Male"],"mesh_terms":["Animals","Brain","Disease Models, Animal","Docosahexaenoic Acids","Leukodystrophy, Globoid Cell","Male","Phenotype","Dinoprost","Fatty Acids, Omega-3","Dietary Supplements","Lipid Metabolism","Mice"],"keywords":["Polyunsaturated fatty acid","Disease","Phenotype","Mediator","Docosahexaenoic acid","Biology","Food science","Chemistry","Biochemistry","Endocrinology","Internal medicine","Fatty acid","Medicine","Gene","Brain","Isoprostanes","Resolvins","Fatty Acid Profile","Krabbe Disease","Omega-3 Pufa","Omega-3 Enriched Diet"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"omim"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T15:58:57.683668Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}