{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:06:29Z","timestamp":1789376789224,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/Y010949\/1"],"award-info":[{"award-number":["MR\/Y010949\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cytoskeleton"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin\u20101 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.<\/jats:p>","DOI":"10.1002\/cm.70204","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:53:08Z","timestamp":1789375988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperactive\n                    <scp>KIF5A<\/scp>\n                    in Neurodegeneration"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4250-7216","authenticated-orcid":false,"given":"David","family":"Villarroel\u2010Campos","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"UK Dementia Research Institute, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-9045","authenticated-orcid":false,"given":"James N.","family":"Sleigh","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"UK Dementia Research Institute, University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.199866"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110598"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.264245"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.04.010"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx370"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111433"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.105713"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201007096\u20105"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010025\u201002277\u2010x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24744"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702752"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw9997"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2774"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201703201"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","unstructured":"Kambara T. L.Rao Y.Yamagishi et\u00a0al.2025.\u201cEnhanced Axonal Transport in Large Vertebrates: KIF5A Adaptations in Giraffes and Pythons.\u201dPreprint bioRxiv May 5.https:\/\/doi.org\/10.1101\/2025.05.04.652084.","DOI":"10.1101\/2025.05.04.652084"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.01.048"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201070543\u2010y"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","unstructured":"Le P. N. K.Lal S.Xu et\u00a0al.2025.\u201cKIF5A Binds RNA to Orchestrate Synaptic mRNA Localization and Stress Granules in ALS.\u201dPreprint bioRxiv November 2.https:\/\/doi.org\/10.1101\/2025.10.31.685813.","DOI":"10.1101\/2025.10.31.685813"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","unstructured":"Liew Y.\u2010T. D. M. D.Bailey W.Cairns et\u00a0al.2025.\u201cDifferent Mechanisms Link Gain and Loss of Kinesin Functions to Axonal Degeneration.\u201dPreprint bioRxiv March 25.https:\/\/doi.org\/10.1101\/2024.12.31.630930.","DOI":"10.1101\/2024.12.31.630930"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.70059"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2016.06.009"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065235"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2346"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12936"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.107503"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.02.027"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154234"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddad134"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106148"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200362"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12831"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.068247"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010019\u20100257\u20102"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2026.114875"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1236815"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0562\u201023.2023"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20253135"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.70496"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.04.046"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522416113"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44318\u2010024\u201000118\u20100"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010024\u201000780\u20106"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1658\u201024.2025"}],"container-title":["Cytoskeleton"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cm.70204","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cm.70204","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cm.70204","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:53:12Z","timestamp":1789375992000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cm.70204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":43,"alternative-id":["10.1002\/cm.70204"],"URL":"https:\/\/doi.org\/10.1002\/cm.70204","archive":["Portico"],"relation":{},"ISSN":["1949-3584","1949-3592"],"issn-type":[{"value":"1949-3584","type":"print"},{"value":"1949-3592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"assertion":[{"value":"2026-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70204"}}