{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:13:19Z","timestamp":1787015599412,"version":"build-2736575974"},"reference-count":71,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["03592\u20102021 RGPIN"],"award-info":[{"award-number":["03592\u20102021 RGPIN"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["06577\u20102018 RGPIN"],"award-info":[{"award-number":["06577\u20102018 RGPIN"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009017","name":"ALS Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009017","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 159781"],"award-info":[{"award-number":["PJT 159781"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT 162431"],"award-info":[{"award-number":["PJT 162431"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is a disease influenced by a complex interplay of age, genetics, and sex. Most ALS cases are sporadic, and individuals with this disease show elevated levels of TDP\u201043 in their central nervous system and aggregated cytoplasmic inclusions containing TDP\u201043 in neurons. Misfolded and aggregated proteins like TDP\u201043 can be refolded or marked for degradation by molecular chaperones and their co\u2010chaperone partners. In this study, we use a mouse model of ALS that mildly overexpresses human wild\u2010type TDP\u201043 in neurons to explore how aging affects the onset of motor abnormalities and proteinopathy in male and female mice. We found that the age\u2010dependent onset of motor symptoms is more pronounced in male mice, despite both sexes sharing similar TDP\u201043 pathology. Further, we found that reducing the activity of STI1, an Hsp90 co\u2010chaperone, was associated with reduced mislocalized TDP\u201043 in the brain and spinal cord and partially rescued some motor deficits. By contrast, overexpressing STI1 seemed to be deleterious, exacerbating the levels of C\u2010terminal TDP\u201043 fragments in the cytoplasm, worsening motor abnormalities and reducing lifespan. Our findings reveal that sex is a key biological factor in an ALS mouse model of TDP\u201043 overexpression and provide novel insights on the role of STI1 and proteostasis in mediating TDP\u201043 pathology.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70204-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70204","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T10:11:02Z","timestamp":1755943862000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Longitudinal Study of Sex Differences in a\n                    <scp>TDP<\/scp>\n                    \u201043 Mouse Model Reveals\n                    <scp>STI1<\/scp>\n                    Regulation of\n                    <scp>TDP<\/scp>\n                    \u201043 Proteinopathy and Motor Deficits"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7203-2929","authenticated-orcid":false,"given":"Vladislav","family":"Novikov","sequence":"first","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"},{"name":"Graduate Program in Neuroscience The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latiyah T. C.","family":"Timothy","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"},{"name":"Graduate Program in Neuroscience The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Fan","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Sadek","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew F.","family":"Cowan","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M.","family":"Onuska","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"},{"name":"Graduate Program in Neuroscience The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Duennwald","sequence":"additional","affiliation":[{"name":"Department of Anatomy &amp; Cell Biology The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania F.","family":"Prado","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"},{"name":"Graduate Program in Neuroscience The University of Western Ontario  London Ontario Canada"},{"name":"Department of Anatomy &amp; Cell Biology The University of Western Ontario  London Ontario Canada"},{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3028-5778","authenticated-orcid":false,"given":"Marco A. M.","family":"Prado","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario  London Ontario Canada"},{"name":"Graduate Program in Neuroscience The University of Western Ontario  London Ontario Canada"},{"name":"Department of Anatomy &amp; Cell Biology The University of Western Ontario  London Ontario Canada"},{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry The University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2016.00310"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2008.09.024"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201014399\u20105"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13\u2010232280"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2012.706303"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1603471"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010015\u20100271\u20106"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010012\u20100979\u20103"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww028"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010023\u201000640\u20109"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010021\u201001159\u2010w"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.12.045"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010011\u20109320\u20107"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01272-7"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597\u2010021\u201001054\u2010y"},{"key":"e_1_2_9_17_1","unstructured":"Fox J. G. S. W.Barthold M. T.Davisson et\u00a0al.2007.\u201cThe Mouse in Biomedical Research. Normative Biology Husbandry and Models.\u201d"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00304"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10317"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201014082\u20105"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13910"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010013\u20108427\u20105"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010015\u20101486\u20100"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010022\u201002491\u20108"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010020\u201001013\u20105"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14882"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002645R"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.03.024"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21147"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(10)70195\u20102"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.06.033"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017611"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215381109"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.14393"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx274"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.06.007"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073944"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3214\u201013.2013"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2020.113608"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201000625\u20108"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00025"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13625"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19807"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201053178\u20105"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.03.032"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000193"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.17389"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101326\u201010\u20101"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201045646\u20109"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201023187\u20109"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3233\/NRE\u2010182531"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197674"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003459107"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041\u2010016\u20100191\u20109"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.71"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111313"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006\u20108993(02)02568\u20104"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2020.581374"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583\u2010022\u201000564\u2010x"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010019\u201000808\u20102"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15967"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708202"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.11.003"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2001.0443"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201076070\u2010w"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00123"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912417107"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010019\u201009652\u2010y"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1630\u201010.2010"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.697621"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101326\u20105\u201033"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2016.00033"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.70204","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T10:33:55Z","timestamp":1756463635000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.70204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":71,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1111\/jnc.70204"],"URL":"https:\/\/doi.org\/10.1111\/jnc.70204","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/JNC.70204\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.70204\/v1\/review1","asserted-by":"object"}]},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2025-02-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70204"}}