{"doi":"10.1101/gad.256644.114","title":"Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models","abstract":"<jats:p>Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice.</jats:p>","journal":"Genes &amp; Development","year":2015,"id":17494,"datarank":5.927268079953064,"base_score":5.0238805208462765,"endowment":5.0238805208462765,"self_citation_contribution":0.7535820781269416,"citation_network_contribution":5.173686001826122,"self_endowment_contribution":0.7535820781269416,"citer_contribution":5.173686001826122,"corpus_percentile":null,"corpus_rank":null,"citation_count":151,"citer_count":133,"citers_with_citation_signal":116,"citers_with_endowment":116,"datacite_reuse_total":4,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":124977,"name":"Ying Hsiu Liu","orcid":null,"position":1,"is_corresponding":false},{"id":124978,"name":"Kentaro Sahashi","orcid":null,"position":2,"is_corresponding":false},{"id":124979,"name":"Frank Rigo","orcid":null,"position":3,"is_corresponding":false},{"id":124980,"name":"C. Frank Bennett","orcid":"0000-0001-9887-6251","position":4,"is_corresponding":false},{"id":3657,"name":"Adrian R. Krainer","orcid":null,"position":5,"is_corresponding":false},{"id":124975,"name":"Yimin Hua","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.0238805208462765,"endowment":5.0238805208462765,"datacite_reuse_total":4,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25583329","pmcid":"PMC4318145","openalex_id":"https://openalex.org/W2170787818","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"R37 GM42699","title":null},{"funder_name":"CSHL Shared Resources","grant_id":"5P30CA045508","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81271423","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81471298","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM042699","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA045508","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R37 GM042699","title":null},{"funder_name":"National Institutes of Health","grant_id":"3P30CA045508-08S1","title":"CSHL CANCER CENTER SUPPORT GRANT"},{"funder_name":"National Institutes of Health","grant_id":"5R37GM042699-28","title":"Biochemistry of Pre-mRNA Splicing"}],"total_grants":9,"fwci":null,"citation_percentile":null,"influential_citations":6,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":15},{"year":2016,"count":24},{"year":2017,"count":17},{"year":2018,"count":11},{"year":2019,"count":16},{"year":2020,"count":16},{"year":2021,"count":7},{"year":2022,"count":13},{"year":2023,"count":11},{"year":2024,"count":9},{"year":2025,"count":9},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"http://genesdev.cshlp.org/content/29/3/288.full.pdf","host_type":"journal"},{"url":"http://genesdev.cshlp.org/content/29/3/288.full.pdf","host_type":"GOLD"},{"url":"http://genesdev.cshlp.org/content/29/3/288.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1101/gad.256644.114","host_type":"publisher"},{"url":"https://doi.org/10.1101/gad.256644.114","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25583329","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4318145","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4318145","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4318145?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1101/gad.256644.114","host_type":""},{"url":"https://dx.doi.org/10.1101/gad.256644.114","host_type":""}],"fields_of_study":["Neurogenetic and Muscular Disorders Research","RNA modifications and cancer","Congenital Anomalies and Fetal Surgery","Biology","Medicine","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","Central Nervous System","Disease Models, Animal","Genetic Therapy","Mice","Mice, Transgenic","Motor Neurons","Muscular Atrophy, Spinal","Oligonucleotides, Antisense","Phenotype","SMN Complex Proteins"],"mesh_terms":["Animals","Central Nervous System","Disease Models, Animal","Mice, Transgenic","Motor Neurons","Muscular Atrophy, Spinal","Phenotype","Genetic Therapy","Oligonucleotides, Antisense","Mice","SMN Complex Proteins"],"keywords":["SMA*","Spinal muscular atrophy","Biology","Motor neuron","Genetically modified mouse","Neuroscience","Transgene","Spinal cord","Gene","Genetics","Antisense oligonucleotide","Mouse Models","Smn2","Smn","Central Nervous System","Motor Neurons","Mice, Transgenic","SMN Complex Proteins","Genetic Therapy","Oligonucleotides, Antisense","Muscular Atrophy, Spinal","Disease Models, Animal","Mice","Phenotype","Animals","Research Paper"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.12276782.v1","title":"Additional file 1 of SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.12276782","title":"Additional file 1 of SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.12276797.v1","title":"Additional file 3 of SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.12276797","title":"Additional file 3 of SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-02T19:09:19.624628Z","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,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}