{"doi":"10.1101/2023.09.14.557673","title":"Linking <i>Gba1</i> E326K mutation to microglia activation and mild age-dependent dopaminergic Neurodegeneration","abstract":"Abstract Mutations in the GBA1 gene have been identified as a prevalent genetic risk factor for Parkinson’s disease (PD). GBA1 mutations impair enzymatic activity, leading to lysosomal dysfunction and elevated levels of α-synuclein (α-syn). While most research has primarily focused on GBA1’s role in promoting synucleinopathy, emerging evidence suggests that neuroinflammation may be a key pathogenic alteration caused by GBA1 deficiency. To examine the molecular mechanism underlying GBA1 deficiency-mediated neuroinflammation, we generated Gba1 E326K knock-in (KI) mice using the CRISPR/Cas9 technology, which is linked to an increased risk of PD and dementia with Lewy bodies (DLB). In the ventral midbrain and hippocampus of 24-month-old Gba1 E326K KI mice, we found a moderate decline in GBA1 enzymatic activity, a buildup of glucosylceramide, and an increase in microglia density. Furthermore, we observed increased levels of pro-inflammatory cytokines and formation of reactive astrocytes in primary microglia and astrocytes, respectively, cultured from Gba1 E326K KI mice following treatment with pathologic α-syn preformed fibrils (PFF). Additionally, the gut inoculation of α-syn PFF in Gba1 E326K KI mice significantly enhanced the accumulation of Lewy bodies in the dentate gyrus of the hippocampus, accompanied by aggravated neuroinflammation and exacerbated non-motor symptoms. This research significantly enhances our understanding of the Gba1 E326K mutation’s involvement in neuroinflammation and the cell-to-cell transmission of pathogenic α-syn in the brain, thereby opening new therapeutic avenues.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395084,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"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":922859,"name":"Hye Guk Ryu","orcid":"0000-0002-5901-1316","position":1,"is_corresponding":false},{"id":922861,"name":"Hyeonwoo Park","orcid":"0000-0003-2562-4656","position":2,"is_corresponding":false},{"id":624195,"name":"Saebom Lee","orcid":"0000-0001-9450-1620","position":3,"is_corresponding":false},{"id":747922,"name":"Namshik Kim","orcid":null,"position":4,"is_corresponding":false},{"id":624196,"name":"Seung‐Hwan Kwon","orcid":"0000-0002-5862-1630","position":5,"is_corresponding":false},{"id":1169897,"name":"Shi‐Xun Ma","orcid":"0000-0002-4208-9248","position":6,"is_corresponding":false},{"id":922863,"name":"Sangjune Kim","orcid":"0000-0003-3052-3163","position":7,"is_corresponding":false},{"id":604404,"name":"Han Seok Ko","orcid":null,"position":8,"is_corresponding":false},{"id":922860,"name":"Sin Ho Kweon","orcid":"0000-0002-9363-6010","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:19:18.686170Z","pmid":"37745332","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":[]}