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TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43\n                    <jats:sup>\u2206NLS<\/jats:sup>\n                    ) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate molecular changes associated with disease-relevant phenotypes. We found that in addition to previously reported dramatic motor decline, rNLS8 mice also develop extra-motor phenotypes consistent with FTD, including disinhibition-like and anxiety-like behaviours, and social interaction impairments. These changes began in the earliest disease stages and remained readily detectable even when rNLS8 mice became severely motor impaired. Notably, extra-motor deficits persisted in rNLS8 mice that had recovered motor function upon hTDP-43\n                    <jats:sup>\u2206NLS<\/jats:sup>\n                    transgene suppression. This correlates with widespread mis-splicing of RNA in rNLS8 cortex at disease onset with n\u2009=\u2009814 genes showing differential exon usage, a molecular phenotype of TDP-43 loss of function. Mis-splicing persists in the rNLS8 cortex in recovery and may represent lasting impacts of cytoplasmic TDP-43 expression. Further, proteomics analysis of the cortex of rNLS8 mice revealed depletion of synaptic proteins, particularly those involved in glutamatergic signalling pathways, which also persisted following hTDP-43\n                    <jats:sup>\u2206NLS<\/jats:sup>\n                    transgene suppression. Similar changes to the glutamatergic pathway were detected in transcriptomic and proteomic datasets from human ALS and FTD post-mortem cortex. Our findings suggest that targeting glutamatergic synaptic components may be an avenue to correct extra-motor deficits associated with TDP-43 pathology.\n                  <\/jats:p>","DOI":"10.1186\/s40478-025-02150-5","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T18:44:29Z","timestamp":1766342669000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synaptic changes contribute to persistent extra-motor behaviour deficits in amyotrophic lateral sclerosis"],"prefix":"10.1186","volume":"14","author":[{"given":"Wei","family":"Luan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"San Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Madrid San Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maize C.","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Vassallu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Venturato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip K.","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heledd","family":"Brown-Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adekunle T.","family":"Bademosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Jia","family":"Chye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao Yu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Harutyunyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu Sheen","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Blizzard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Scotter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel M.","family":"Igaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam K.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"issue":"10","key":"2150_CR1","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1111\/ene.14393","volume":"27","author":"P Masrori","year":"2020","unstructured":"Masrori P, Van Damme P (2020) Amyotrophic lateral sclerosis: a clinical review. 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