{"doi":"10.1101/2020.03.25.007542","title":"Brainstem development requires galactosylceramidase and is critical for the pathogenesis of Krabbe Disease","abstract":"Abstract Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. We hypothesized that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induced ubiquitous GALC ablation ( Galc -iKO) at various postnatal timepoints and identified a critical period of vulnerability to GALC ablation between P4-6. Early Galc -iKO induction caused a worse KD phenotype, higher psychosine levels, and a significantly shorter life-span. Intriguingly, GALC expression peaks during this critical developmental period. Further analysis revealed a novel cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126429,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":463206,"name":"Conlan Kreher","orcid":"0000-0001-9952-9374","position":1,"is_corresponding":false},{"id":464473,"name":"Jacob Favret","orcid":null,"position":2,"is_corresponding":false},{"id":305928,"name":"Ernesto R. Bongarzone","orcid":"0000-0003-1664-6634","position":3,"is_corresponding":false},{"id":463207,"name":"Lawrence Wrabetz","orcid":"0000-0003-3360-1032","position":4,"is_corresponding":false},{"id":463208,"name":"M. Laura Feltri","orcid":"0000-0002-2276-9182","position":5,"is_corresponding":false},{"id":463209,"name":"Daesung Shin","orcid":"0000-0001-5285-3820","position":6,"is_corresponding":false},{"id":463205,"name":"Nadav I. Weinstock","orcid":"0000-0002-9065-4176","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","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":[]}