{"doi":"10.1101/2023.08.28.555106","title":"PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport","abstract":"Abstract ALS is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of fALS cases. Studying the mechanisms by which mutant FUS is toxic to neurons may provide insight into the pathogenesis of both familial and sporadic forms of ALS. Here we identify Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS in vivo , looking from fly to human. PP2A-C and GSK3β inhibition rescued FUS-induced toxicity in Drosophila and disease-relevant phenotypes in human iPSC-derived spinal motor neurons (sMNs). In both Drosophila and human iPSC-sMNs, we observed reduced GSK3β inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3β hyperactivity. We found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation, and in synergy they modulate mitochondrial transport through the motor protein kinesin. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3 and kinesin in FUS-associated ALS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":410889,"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":0.9628,"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":1191064,"name":"Jolien Steyaert","orcid":"0000-0001-5587-706X","position":1,"is_corresponding":false},{"id":1191405,"name":"Wendy Scheveneels","orcid":null,"position":2,"is_corresponding":false},{"id":1191065,"name":"Adrià Sicart","orcid":"0009-0004-6102-9381","position":3,"is_corresponding":false},{"id":1191066,"name":"Katarina Stoklund Dittlau","orcid":"0000-0003-2776-2892","position":4,"is_corresponding":false},{"id":1191406,"name":"Adriana Margarida Barbosa Correia","orcid":null,"position":5,"is_corresponding":false},{"id":1191407,"name":"Arun Pal","orcid":null,"position":6,"is_corresponding":false},{"id":1098419,"name":"Andreas Hermann","orcid":"0000-0002-7364-7791","position":7,"is_corresponding":false},{"id":299345,"name":"Philip Van Damme","orcid":"0000-0002-4010-2357","position":8,"is_corresponding":false},{"id":237395,"name":"Thomas G. Moens","orcid":"0000-0002-4783-6257","position":9,"is_corresponding":false},{"id":237403,"name":"Ludo Van Den Bosch","orcid":"0000-0003-0104-4067","position":10,"is_corresponding":false},{"id":1191063,"name":"Paraskevi Tziortzouda","orcid":"0000-0002-6969-8158","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:21:38.940853Z","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":[]}