{"doi":"10.1371/journal.pone.0294731","title":"Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice","abstract":"Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.","journal":"PLoS ONE","year":2023,"id":353341,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":669368,"name":"Kathleen M. Schoch","orcid":"0000-0001-6710-5147","position":1,"is_corresponding":false},{"id":895485,"name":"Anthony Verbeck","orcid":null,"position":2,"is_corresponding":false},{"id":564127,"name":"Grant Galasso","orcid":null,"position":3,"is_corresponding":false},{"id":242218,"name":"Hao Chen","orcid":"0000-0002-8874-0673","position":4,"is_corresponding":false},{"id":560928,"name":"Sarah E. Smith","orcid":"0000-0003-1570-5700","position":5,"is_corresponding":false},{"id":480212,"name":"Anna Oldenborg","orcid":null,"position":6,"is_corresponding":false},{"id":250919,"name":"Timothy M. Miller","orcid":"0000-0002-3424-5511","position":7,"is_corresponding":false},{"id":301876,"name":"Celeste M. Karch","orcid":"0000-0002-6854-5547","position":8,"is_corresponding":false},{"id":1099588,"name":"Azad Bonni","orcid":"0009-0003-5409-214X","position":9,"is_corresponding":false},{"id":453600,"name":"Abhirami K. Iyer","orcid":"0000-0003-1914-6045","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:58.542950Z","pmid":"38015828","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":[]}