{"doi":"10.1101/2025.10.10.681644","title":"Complement Factor H and its <i>C. elegans</i> homolog regulate IFT52/OSM-6 and CNG channel localization in sensory neurons","abstract":"ABSTRACT Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive degeneration of retinal photoreceptors. Current disease models propose AMD pathogenesis is a consequence of cytolytic damage and tissue inflammation that result from defective repression of alternative complement pathway activity by complement factor H (CFH). However, recent studies demonstrate functions for CFH that are outside of its established role in the alternative complement pathway, suggesting that novel CFH-mediated mechanisms may influence AMD initiation and progression. Our previous demonstration that CFH and its nematode homolog, CFH-1, modulate inversin/NPHP-2 accumulation in vertebrate photoreceptor and C. elegans sensory neuron cilia during aging suggests that AMD patients with CFH loss-of-function mutations have cilia defects that may contribute to photoreceptor dysfunction. Here, we investigate the consequences of CFH and CFH-1 loss-of-function mutations on the dynamics and localization of intraflagellar transport (IFT) train and visual cycle components in these cells. In C. elegans sensory neurons, IFTB1 components IFT52/OSM-6 and IFT88/OSM-5 are transported at similar rates in WT animals but IFT52/OSM-6 transport slows significantly in cfh-1 mutant animals while IFT88/OSM-5 is unaffected. Defective localization of IFT52/OSM-6 in photoreceptors of CFH knockout mice and in human photoreceptors from AMD high-risk CFH Y402H homozygotes, suggest an evolutionarily conserved role for CFH in promoting IFT52/OSM-6 transport and localization in sensory neuron cilia. In addition, distribution of CNG channel subunits in C. elegans cfh-1 mutant sensory neurons and CFH Y402H high-risk human photoreceptors are distinct from their WT and Y402 low-risk counterparts. Together, the data indicate previously unappreciated functions for CFH in IFT train organization and cilia protein localization and suggest a novel mechanism for photoreceptor segment thinning, an early AMD biomarker that has been linked to CFH high-risk variants.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559298,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"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":0.9542,"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":481482,"name":"Katarzyna A. Hussey","orcid":"0000-0002-5046-2815","position":1,"is_corresponding":false},{"id":816324,"name":"Joanna F. D. Hagen","orcid":"0000-0002-7576-6137","position":2,"is_corresponding":false},{"id":497469,"name":"Zeljka Smit‐McBride","orcid":"0000-0003-0275-8088","position":3,"is_corresponding":false},{"id":1460525,"name":"M. Rajashekhar Moorthy","orcid":"0009-0000-3661-4942","position":4,"is_corresponding":false},{"id":741171,"name":"Joanne Aiko Matsubara","orcid":"0000-0002-3689-3117","position":5,"is_corresponding":false},{"id":445832,"name":"Martin F. Flajnik","orcid":"0000-0002-2792-5084","position":6,"is_corresponding":false},{"id":259949,"name":"Robert J. Johnston","orcid":"0000-0002-5775-6218","position":7,"is_corresponding":false},{"id":741172,"name":"Bruce E. Vogel","orcid":"0000-0002-2576-3843","position":8,"is_corresponding":false},{"id":678224,"name":"Yumiko Oshima","orcid":"0009-0001-7766-656X","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41278837","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":[]}