{"doi":"10.1101/2025.06.23.661126","title":"Bidirectional regulation of glycoprotein nonmetastatic melanoma protein B by β-glucocerebrosidase deficiency in <i>GBA1</i> isogenic dopaminergic neurons from a patient with Gaucher disease and parkinsonism","abstract":"Abstract Variants in GBA1 are common genetic risk factors for several synucleinopathies. The increased risk has been attributed to the toxic effects of misfolded glucocerebrosidase (GCase) (gain-of-function), and the accumulation of lipid substrates due to reduced enzyme activity (loss-of-function). To delineate GBA1 pathogenicity, an iPSC line was generated from a patient with both type 1 Gaucher disease ( GBA1 : N370S/N370S; p.N409S/p.N409S) and Parkinson disease (PD). From this line, we created a reverted wild-type (WT) line and a GBA1 knockout (KO) line to eliminate misfolded GCase and intensify lipid accumulation. N370S/N370S and KO dopaminergic neurons (DANs) exhibited decreasing GCase levels and progressive accumulation of lipid substrates compared to WT DANs. Notably, the expression of GPNMB , whose levels correlate with PD risk, was upregulated by the mild lipid accumulation in N370S/N370S DANs but disrupted in KO DANs. These findings refine the loss-of-function mechanism by associating PD risk levels of GPNMB with lipid levels specific to GBA1 risk variants.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":569054,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1335606,"name":"Charis Ma","orcid":null,"position":1,"is_corresponding":false},{"id":314060,"name":"Richard Sam","orcid":"0000-0002-2107-0329","position":2,"is_corresponding":false},{"id":892091,"name":"Jens Lichtenberg","orcid":"0000-0002-0023-4937","position":3,"is_corresponding":false},{"id":615212,"name":"Tiffany Chen","orcid":"0000-0003-2546-2941","position":4,"is_corresponding":false},{"id":751093,"name":"Ying Hao","orcid":"0000-0001-5053-4850","position":5,"is_corresponding":false},{"id":1473718,"name":"Yuxiu Li","orcid":"0000-0002-5227-421X","position":6,"is_corresponding":false},{"id":1453316,"name":"Isabelle Kowal","orcid":null,"position":7,"is_corresponding":false},{"id":1335607,"name":"Kate Andersh","orcid":null,"position":8,"is_corresponding":false},{"id":567365,"name":"Yue Qi","orcid":"0000-0003-1914-8710","position":9,"is_corresponding":false},{"id":1335604,"name":"Gani Perez","orcid":null,"position":10,"is_corresponding":false},{"id":878509,"name":"Ellen Hertz","orcid":"0000-0002-0916-3557","position":11,"is_corresponding":false},{"id":493642,"name":"Yan Li","orcid":"0000-0003-3673-181X","position":12,"is_corresponding":false},{"id":489257,"name":"Darian Williams","orcid":"0000-0002-4572-3056","position":13,"is_corresponding":false},{"id":287614,"name":"Mark J. Henderson","orcid":"0000-0001-8590-7338","position":14,"is_corresponding":false},{"id":20064,"name":"Morgan Park","orcid":null,"position":15,"is_corresponding":false},{"id":308930,"name":"Xuntian Jiang","orcid":"0000-0001-9048-7294","position":16,"is_corresponding":false},{"id":681359,"name":"Pilar Álvarez Jerez","orcid":"0000-0002-5812-1898","position":17,"is_corresponding":false},{"id":252390,"name":"Cornelis Blauwendraat","orcid":"0000-0001-9358-8111","position":18,"is_corresponding":false},{"id":305686,"name":"Ellen Sidransky","orcid":"0000-0002-3019-8500","position":19,"is_corresponding":false},{"id":493538,"name":"Yu Chen","orcid":"0000-0001-5438-7309","position":20,"is_corresponding":false},{"id":953395,"name":"Chase Chen","orcid":"0000-0003-1016-0844","position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40667145","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":[]}