{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T16:15:26Z","timestamp":1786637726085,"version":"build-2736575974"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFA1108000"],"award-info":[{"award-number":["2024YFA1108000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["STI2030\u2010Major Projects\u20102021ZD0202400"],"award-info":[{"award-number":["STI2030\u2010Major Projects\u20102021ZD0202400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing Municipality","doi-asserted-by":"publisher","award":["CSTB2023NSCQ\u2010MSX0217"],"award-info":[{"award-number":["CSTB2023NSCQ\u2010MSX0217"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301774"],"award-info":[{"award-number":["82301774"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hereditary spastic paraplegias (HSPs) are monogenic neurodegenerative disorders, and\n                      <jats:italic>SPAST<\/jats:italic>\n                      mutations causing spastic paraplegia type 4 (SPG4) represent the most common form of HSP.\n                      <jats:italic>SPAST<\/jats:italic>\n                      mutations elevate SPASTIN protein levels beyond haploinsufficiency, but the mechanisms and downstream consequences are unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identified a de novo\n                      <jats:italic>SPAST<\/jats:italic>\n                      missense variant (p.I344E) in a young Chinese female with SPG4. Wild\u2010type (WT) and mutant (I344E\/K)\n                      <jats:italic>SPAST<\/jats:italic>\n                      constructs were expressed in HEK293 for biochemical and functional assays including cycloheximide chase, ubiquitination analysis, and immunofluorescence. Leveraging somatic cell reprogramming and CRISPR\u2010based gene editing, we generated patient\u2010derived induced pluripotent stem cells (iPSCs) and their isogenic controls. Both lines were differentiated into cerebral organoids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>I344E\/K\u2010SPASTIN exhibited markedly higher steady\u2010state levels than WT\u2010SPASTIN owing to impaired ubiquitin\u2010proteasome\u2010mediated degradation; the I344E variant showed the greatest accumulation. Mutant SPASTIN mislocalized in cells, displayed diminished microtubule\u2010severing activity, and elevated acetylated tubulin\u2014phenotypes that were rescued by overexpression of WT\u2010SPASTIN. In patient cerebral organoids, the I344E mutation led to increased p62\/SQSTM1 aggregates, reduced autophagic flux, and enhanced neuronal death. Rapamycin restored autophagy, decreased p62 levels, and reduced cell death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study provides evidence linking autophagy dysfunction to SPG4 pathogenesis and demonstrates that the I344E mutation acts through a gain\u2010of\u2010function mechanism. These findings challenge the prevailing haploinsufficiency model and implicate autophagy modulation as a potential therapeutic strategy for SPG4 and possibly other HSPs. \u00a9 2025 International Parkinson and Movement Disorder Society.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70150","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T09:26:32Z","timestamp":1765963592000},"page":"625-637","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reversing Autophagy Inhibition Ameliorates Neurodegeneration in Hereditary Spastic Paraplegia Caused by a Degradation\u2010Resistant\n                    <scp>\n                      <i>SPAST<\/i>\n                    <\/scp>\n                    Mutation"],"prefix":"10.1002","volume":"41","author":[{"given":"Dingyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education); Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhe","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education); Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education); Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education); Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nong","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Fan","sequence":"additional","affiliation":[{"name":"Central Laboratory Chongqing University Fuling Hospital, Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders  Chongqing China"},{"name":"Department of Rehabilitation, Jiangxi Children's Medical Center, Jiangxi Provincial Key Laboratory of Birth Defect for Prevention and Control  Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-6871","authenticated-orcid":false,"given":"Tongfei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education); Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031697"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2021.06.006"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/15472"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv178"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-019-0257-3"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2022.03.019"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100380200068"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.07.009"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.09.015"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2025.01.010"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101530"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-00433-w"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1783-0_15"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000228242.53336.90"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2021.5051"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E17-01-0047"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.70105"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.94583"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06154-8"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-016-0031-z"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.12332"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00308-7"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17256"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0201-5"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201609033"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02135-w"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/gpbjnl\/qzae047"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae978"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70150","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mds.70150","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T15:16:57Z","timestamp":1786634217000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.70150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/mds.70150"],"URL":"https:\/\/doi.org\/10.1002\/mds.70150","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]},"assertion":[{"value":"2025-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}