{"doi":"10.1016/j.celrep.2023.113244","title":"α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity","abstract":"Anomalous aggregation of α-synuclein (α-Syn) is a pathological hallmark of many degenerative synucleinopathies including Lewy body dementia (LBD) and Parkinson's disease (PD). Despite its strong link to disease, the precise molecular mechanisms that link α-Syn aggregation to neurodegeneration have yet to be elucidated. Here, we find that elevated α-Syn leads to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P 2 , which precipitates α-Syn aggregation and drives toxic increases in mitochondrial Ca 2+ and reactive oxygen species leading to neuronal death. Upstream of this toxic signaling pathway is PIP5K1γ, whose abundance and localization is enhanced at the PM by α-Syn-dependent increases in ARF6. Selective inhibition of PIP5K1γ or knockout of ARF6 in neurons rescues α-Syn aggregation and cellular phenotypes of toxicity. Collectively, our data suggest that modulation of phosphoinositide metabolism may be a therapeutic target to slow neurodegeneration for PD and other related neurodegenerative disorders.","journal":"Cell Reports","year":2023,"id":346882,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":481394,"name":"Maria Casas","orcid":"0000-0002-5246-8874","position":1,"is_corresponding":false},{"id":694186,"name":"Candice Kutchukian","orcid":"0000-0003-1142-7109","position":2,"is_corresponding":false},{"id":1088293,"name":"Sara Creus Sánchez","orcid":null,"position":3,"is_corresponding":false},{"id":516152,"name":"Melissa R. Pergande","orcid":"0000-0003-1197-4057","position":4,"is_corresponding":false},{"id":421639,"name":"Stephanie M. Cologna","orcid":"0000-0002-3541-3361","position":5,"is_corresponding":false},{"id":252457,"name":"Sergi Simó","orcid":"0000-0002-8344-0313","position":6,"is_corresponding":false},{"id":632995,"name":"Rose E. Dixon","orcid":"0000-0003-0655-690X","position":7,"is_corresponding":false},{"id":355958,"name":"Eamonn J. Dickson","orcid":"0000-0001-8619-7630","position":8,"is_corresponding":false},{"id":698903,"name":"Jonathan D. Horvath","orcid":null,"position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":null,"created_at":"2026-07-19T01:11:53.085356Z","pmid":"37838947","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":[]}