{"doi":"10.1016/j.nbd.2024.106593","title":"Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism","abstract":null,"journal":"Neurobiology of Disease","year":2024,"id":612523,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"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":1577176,"name":"W.N. Hahn","orcid":null,"position":1,"is_corresponding":false},{"id":1577177,"name":"T.D. McCaffery","orcid":null,"position":2,"is_corresponding":false},{"id":1577178,"name":"T.E. Moors","orcid":null,"position":3,"is_corresponding":false},{"id":1366678,"name":"X. Zhang","orcid":"0009-0009-2791-1684","position":4,"is_corresponding":false},{"id":1577179,"name":"P. Svenningsson","orcid":null,"position":5,"is_corresponding":false},{"id":1577181,"name":"D.J. Selkoe","orcid":null,"position":6,"is_corresponding":false},{"id":1577182,"name":"S. Fanning","orcid":null,"position":7,"is_corresponding":false},{"id":1577184,"name":"S. Nuber","orcid":null,"position":8,"is_corresponding":false},{"id":1577174,"name":"M.A. Adom","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism","abstract":"Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.elegans αS model. However, assessing LIPE as a potential therapeutic target for progressive PD motor phenotypes has not been investigated. 3K αS mice, representing a biochemical and neuropathological amplification of the E46K fPD-causing mutation, have decreased αS T:M ratios, lipidic aggregates, and a L-DOPA responsive PD-like motor syndrome. Here, we reduced LIPE by crossings of 3K mice with LIPE null mice, which attenuated motor deficits in male LIPE+/− knockdown (LKD)-3K mice. Heterozygous LIPE reduction was associated with an improved αS T:M ratio, and dopaminergic neurotransmitter levels and fiber densities. In female 3K-LKD mice, an increase in pS129+ and larger lipid droplets (LDs) likely decreased the benefits seen in males. Reducing LIPE decreased MUFA release from neutral lipid storage, thereby reducing MUFA in phospholipid membranes with which αS interacts. Our study highlights fatty acid turnover as a therapeutic target for Lewy body diseases and support LIPE as a promising target in males. LIPE regulation represents a novel approach to mitigate PD and DLB risk and treat disease.","is_dataset_classified":null,"base_score":2.772588722239781,"endowment":2.772588722239781,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38971480","pmcid":"PMC11577057","openalex_id":"https://openalex.org/W4400345371","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"RF1 NS109510","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS133243","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS083845","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS109510","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"RF1 NS083845","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R01NS133243-01A1","title":"Mechanistic Dissection of Lipase (LIPE) Regulation of Fatty Acid Homeostasis as a Parkinson's Disease and Lewy Body Dementia Therapeutic Strategy"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS109510-04","title":"Biologically novel mouse models of PD with progressive synucleinopathy and early-onset tremor and motor deficits responsive to L-DOPA"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS083845-05","title":"Biology of Native Alpha-Synuclein Tetramers in Parkinson's Disease"}],"total_grants":8,"fwci":4.1375,"citation_percentile":0.95109315,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":7},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1016/j.nbd.2024.106593","host_type":"journal"},{"url":"https://doi.org/10.1016/j.nbd.2024.106593","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0969996124001931?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0969996124001931?httpAccept=text/plain","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38971480","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11577057","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/en/publications/a0248ad0-9484-4612-bebc-3ef613d49688","host_type":"repository"},{"url":"https://doaj.org/article/b89afb9af5414bbf9818138fce4317af","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11577057/pdf/nihms-2032226.pdf","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/ws/files/156414484/Reducing-the-lipase-lipe-in-mutant--synuclein-mice-improves-parkinson-like-deficits-and-reveals-sex-differences-in-fatt.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11577057","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11577057?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1016/j.nbd.2024.106593","host_type":""}],"fields_of_study":["Parkinson's Disease Mechanisms and Treatments","Adipose Tissue and Metabolism","Metabolism, Diabetes, and Cancer","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","alpha-Synuclein","Mice","Fatty Acids","Female","Male","Parkinson Disease","Sex Characteristics","Sterol Esterase","Mice, Transgenic","Lipid Metabolism","Mice, Inbred C57BL","Mutation"],"mesh_terms":["Animals","Sterol Esterase","Fatty Acids","Female","Male","Mice, Inbred C57BL","Mice, Transgenic","Mutation","Parkinson Disease","Sex Characteristics","Lipid Metabolism","Mice","alpha-Synuclein"],"keywords":["Mutant","Lipase","Biochemistry","Biology","Chemistry","Enzyme","Gene","Hormone-sensitive lipase","Parkinson's Disease","alpha-Synuclein","Lipe","Male","Sex Characteristics","Fatty Acids","Neurosciences. Biological psychiatry. Neuropsychiatry","Parkinson Disease","Mice, Transgenic","Sterol Esterase","Lipid Metabolism","Article","Mice, Inbred C57BL","Mice","Mutation","Animals","Female","RC321-571"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T03:50:17.673578Z","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":[]}