{"doi":"10.1101/2024.05.29.595206","title":"Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia","abstract":"SUMMARY Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn −/− mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn −/− RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486179,"datarank":0.264028075695227,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.02261238883011191,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.02261238883011191,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":642588,"name":"Frederike Cosima Oertel","orcid":"0000-0003-4906-5983","position":1,"is_corresponding":false},{"id":1194701,"name":"An Cheng","orcid":"0000-0002-7816-203X","position":2,"is_corresponding":false},{"id":304543,"name":"Yann Cobigo","orcid":"0000-0002-0354-4092","position":3,"is_corresponding":false},{"id":1329621,"name":"Azeen Keihani","orcid":"0000-0002-9040-6535","position":4,"is_corresponding":false},{"id":1006697,"name":"Daniel J. 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Rosen","orcid":"0000-0001-9281-7402","position":14,"is_corresponding":false},{"id":253908,"name":"Adam L. Boxer","orcid":"0000-0002-1215-5064","position":15,"is_corresponding":false},{"id":58513,"name":"Bruce L. Miller","orcid":"0000-0002-2152-4220","position":16,"is_corresponding":false},{"id":246281,"name":"Ari Green","orcid":"0000-0001-9275-3066","position":17,"is_corresponding":false},{"id":314700,"name":"Fanny M. 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