{"doi":"10.1101/2021.11.23.469650","title":"Astrocytic expression of ALS-causative mutant FUS leads to TNFα-dependent neurodegeneration <i>in vivo</i>","abstract":"ABSTRACT Genetic mutations that cause Amyotrophic Lateral Sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non-neuronal cells is also an important driver of disease. Previously, we demonstrated that mutations in DNA/RNA binding protein Fused in Sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro, via activation of the NF-κB pathway and release of pro-inflammatory cytokine TNFα. Here, we developed an intraspinal cord injection model to test whether astrocyte-specific expression of ALS-causative FUS R521G variant (mtFUS) causes neuronal damage in vivo . We show that mtFUS expression causes TNFα upregulation, motor function deficits, and spinal motor neuron loss. We further demonstrate a lack of phenotype in TNFα knockout animals expressing mtFUS, and prevention of neurodegeneration in mtFUS-transduced animals through administration of TNFα neutralizing antibodies. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS, establish that FUS-ALS astrocytes induce pathogenic changes to motor neurons in vivo , and provide insights identifying FUS-ALS specific potential therapeutic targets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":227825,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9664,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348836,"name":"Kevin McAvoy","orcid":"0000-0002-0025-1921","position":1,"is_corresponding":false},{"id":832127,"name":"Nicolette M. Heinsinger","orcid":"0000-0002-7281-8800","position":2,"is_corresponding":false},{"id":832128,"name":"Angelo C. Lepore","orcid":"0000-0002-5956-6135","position":3,"is_corresponding":false},{"id":832129,"name":"Hristelina Ilieva","orcid":"0000-0001-8318-7533","position":4,"is_corresponding":false},{"id":285353,"name":"Aaron R. Haeusler","orcid":"0000-0001-5566-3707","position":5,"is_corresponding":false},{"id":348844,"name":"Davide Trotti","orcid":"0000-0001-6338-6404","position":6,"is_corresponding":false},{"id":348843,"name":"Piera Pasinelli","orcid":"0000-0002-3385-2707","position":7,"is_corresponding":false},{"id":348835,"name":"Brigid K. Jensen","orcid":"0000-0003-1624-6307","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:46.312854Z","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":[]}