{"doi":"10.1101/2024.09.08.611864","title":"GSK-3β coordinates axonal microtubule organisation through Shot and Tau","abstract":"Abstract Glycogen Synthase Kinase 3β (GSK-3β) is a key coordinator of neuronal development and maintenance; hyperactive GSK-3β is linked to neurodevelopmental and -degenerative diseases and therefore a promising therapeutic target. In neurons, GSK-3β coordinates the cytoskeleton by phosphorylating microtubule-binding proteins. In this study, we found that tight regulation of GSK-3β kinase activity is required for the maintenance of parallel microtubule bundles in Drosophila and rat axons. Up- or down-regulation of GSK-3β led to axons forming pathological swellings in which microtubule bundles disintegrated into disorganised, curled microtubules. We identified the microtubule bundling proteins Shot and Tau as key GSK-3β targets and found that GSK-3β exerted its regulatory effect on microtubule bundling through them. GSK-3β regulates the ability of Shot and Tau to attach to microtubules and/or the plus-end protein Eb1. Mis-regulation of GSK-3β leads to the loss of Eb1–Shot-mediated guidance of polymerising microtubules into parallel bundles, thus causing disorganisation. We propose microtubule disorganisation as a new explanation for how GSK-3β hyperactivity leads to neurodegeneration and why global inhibition of GSK-3β has not been successful in clinical trials for neuronal disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485691,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":1329198,"name":"Lubna Nuhu-Soso","orcid":null,"position":1,"is_corresponding":false},{"id":1329199,"name":"Alex Roof","orcid":null,"position":2,"is_corresponding":false},{"id":960288,"name":"Sanjai Patel","orcid":"0000-0002-8601-8185","position":3,"is_corresponding":false},{"id":1328713,"name":"Hayley Bennett","orcid":"0000-0002-8956-4317","position":4,"is_corresponding":false},{"id":810437,"name":"Antony Adamson","orcid":"0000-0002-5408-0013","position":5,"is_corresponding":false},{"id":424376,"name":"Marvin Bentley","orcid":"0000-0002-1754-0332","position":6,"is_corresponding":false},{"id":1328714,"name":"Gareth J. Evans","orcid":"0000-0003-2573-7001","position":7,"is_corresponding":false},{"id":558832,"name":"Ines Hahn","orcid":"0000-0001-7703-8160","position":8,"is_corresponding":false},{"id":668309,"name":"André Voelzmann","orcid":"0000-0002-7682-5637","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:07:52.536246Z","pmid":"40654684","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":[]}