{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:46:02Z","timestamp":1791521162980,"version":"4.3.4"},"reference-count":43,"publisher":"Wiley","issue":"36","license":[{"start":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T00:00:00Z","timestamp":1751155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T00:00:00Z","timestamp":1751155200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82330041"],"award-info":[{"award-number":["82330041"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92049107"],"award-info":[{"award-number":["92049107"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171258"],"award-info":[{"award-number":["32171258"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cytoplasmic aggregation of transactive response DNA\u2010binding protein 43 (TDP\u201043) is a hallmark of amyotrophic lateral sclerosis (ALS) and occurs in 57% of Alzheimer's disease (AD) cases. TDP\u201043 regulates RNA processing, including cryptic exon splicing. Here, we demonstrate that TDP\u201043 directly controls growth\u2010associated protein (GAP43) expression by binding to its pre\u2010mRNA. Loss or hyperphosphorylation of TDP\u201043 disrupts this binding, leading to the inclusion of cryptic exon\n                    <jats:italic>4a1<\/jats:italic>\n                    , which introduces premature stop codons and reduces GAP43 protein levels. RNA sequencing analysis of ALS and AD brains revealed\n                    <jats:italic>GAP43<\/jats:italic>\n                    downregulation, while\n                    <jats:italic>4a1<\/jats:italic>\n                    is upregulated in AD cases with phosphorylated TDP\u201043. TDP\u201043 knockdown impaired axonal regeneration in induced pluripotent stem cell (iPSC)\u2010derived motor neurons, whereas GAP43 restoration rescued this defect. These findings suggest that the loss of GAP43 contributes to neurodegeneration in ALS and AD. The inclusion of\n                    <jats:italic>GAP43<\/jats:italic>\n                    cryptic exon\n                    <jats:italic>4a1<\/jats:italic>\n                    may serve as a hallmark of TDP\u201043 proteinopathies,\u00a0highlighting a mechanistic link between TDP\u201043 dysfunction and neuronal vulnerability.\n                  <\/jats:p>","DOI":"10.1002\/advs.202412054","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T12:17:58Z","timestamp":1752409078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cryptic Splicing of\n                    <i>GAP43<\/i>\n                    mRNA is a Novel Hallmark of TDP\u201043\u2010Associated ALS and AD"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9161-9420","authenticated-orcid":false,"given":"Mingming","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"},{"name":"Department of Biochemistry and Molecular Biology School of Medicine Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu 226001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongkun","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medicinal Administration Faculty of Health Sciences University of Macau  Macao SAR 999078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Zhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"},{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders Institute of Biomedical Sciences School of Medicine Jianghan University  Wuhan 430056 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Ming","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medicinal Administration Faculty of Health Sciences University of Macau  Macao SAR 999078 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Medicine Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong Jiangsu 226001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5067-043X","authenticated-orcid":false,"given":"Xiaochuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 430030 China"},{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders Institute of Biomedical Sciences School of Medicine Jianghan University  Wuhan 430056 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,29]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1269-z"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab0983"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211577110"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-0333-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2021.02.008"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04436-3"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04424-7"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq5622"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0293-z"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0300-4"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-023-02655-0"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00646-z"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI139741"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg294"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14535"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00296492"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(96)10072-2"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050814"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90197-3"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2013.128"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0715"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.12.008"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abp9556"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00556-5"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.12.014"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818415116"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01346-0"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8413496"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg7162"},{"key":"e_1_2_9_30_1","author":"Bryce\u2010Smith S.","year":"2024","journal-title":"BioRxiv : the Preprint Server For Biology"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002028"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00556-8"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27423-0"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab393"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00062-0"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06405-w"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022111719"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12976"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12775"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-220985"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf6895"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136769"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202412054","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202412054","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202412054","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:13:51Z","timestamp":1785438831000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202412054"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,29]]},"references-count":43,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/advs.202412054"],"URL":"https:\/\/doi.org\/10.1002\/advs.202412054","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,29]]},"assertion":[{"value":"2024-09-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12054"}}