{"doi":"10.1101/2022.01.10.475450","title":"FTY720 requires vitamin B <sub>12</sub> -TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis","abstract":"Summary FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P 1 . Vitamin B 12 (B 12 ) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B 12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes ) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B 12 receptor, by S1P 1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B 12 worsened EAE and eliminated FTY720’s efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B 12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299736,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"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":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":584518,"name":"Yasuyuki Kihara","orcid":"0000-0001-7462-3006","position":1,"is_corresponding":false},{"id":990404,"name":"Aran Groves","orcid":null,"position":2,"is_corresponding":false},{"id":584517,"name":"Manisha Ray","orcid":"0000-0001-7145-6601","position":3,"is_corresponding":false},{"id":469003,"name":"Arjun Saha","orcid":"0000-0003-1198-1820","position":4,"is_corresponding":false},{"id":990050,"name":"Hyeon‐Cheol Lee","orcid":"0000-0002-5493-8112","position":5,"is_corresponding":false},{"id":990051,"name":"Tomomi Furihata","orcid":"0000-0003-3614-9328","position":6,"is_corresponding":false},{"id":772325,"name":"Takehiko Yokomizo","orcid":"0000-0002-5219-1553","position":7,"is_corresponding":false},{"id":356688,"name":"Edward V. Quadros","orcid":"0000-0002-7663-8014","position":8,"is_corresponding":false},{"id":772321,"name":"Richard Rivera","orcid":"0000-0001-6138-3306","position":9,"is_corresponding":false},{"id":38374,"name":"Jerold Chun","orcid":"0000-0003-3964-0921","position":10,"is_corresponding":false},{"id":772320,"name":"Deepa Jonnalagadda","orcid":"0000-0002-1511-8197","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:49.412501Z","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":[]}