{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:24:47Z","timestamp":1790717087893,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,2]],"date-time":"2017-11-02T00:00:00Z","timestamp":1509580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,2]],"date-time":"2017-11-02T00:00:00Z","timestamp":1509580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Several transgenic mouse models have been generated that recapitulate defects in TDP-43 accumulation, thus causing neurodegeneration and behavioural impairments. While aging is the key risk factor for neurodegenerative diseases, the specific effect of aging on phenotypes in TDP-43 transgenic mice has not been investigated. Here, we analyse age-dependent changes in TDP-43 transgenic mice that displayed impaired memory. We found the accumulation of abundant poly-ubiquitinated protein aggregates in the hippocampus of aged TDP-43 transgenic mice. Intriguingly, the aggregates contained some interneuron-specific proteins such as parvalbumin and calretinin, suggesting that GABAergic interneurons were degenerated in these mice. The abundance of aggregates significantly increased with age and with the overexpression of TDP-43. Gene array analyses in the hippocampus and other brain areas revealed dysregulation in genes linked to oxidative stress and neuronal function in TDP-43 transgenic mice. Our results indicate that the interneuron degeneration occurs upon aging, and TDP-43 accelerates age-dependent neuronal degeneration, which may be related to the impaired memory of TDP-43 transgenic mice.<\/jats:p>","DOI":"10.1038\/s41598-017-14966-w","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T15:52:44Z","timestamp":1509119564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["TDP-43 accelerates age-dependent degeneration of interneurons"],"prefix":"10.1038","volume":"7","author":[{"given":"Hitomi","family":"Tsuiji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuyo","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Furuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Yamakage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3174-5684","authenticated-orcid":false,"given":"Masato","family":"Koike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuharu","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-0035","authenticated-orcid":false,"given":"Koji","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,2]]},"reference":[{"key":"14966_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/nn.3584","volume":"17","author":"AE Renton","year":"2014","unstructured":"Renton, A. 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Biochem Biophys Res Commun \n                           351, 602\u2013611 (2006).","journal-title":"Biochem Biophys Res Commun"},{"key":"14966_CR4","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","volume":"79","author":"SC Ling","year":"2013","unstructured":"Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron \n                           79, 416\u2013438 (2013).","journal-title":"Neuron"},{"key":"14966_CR5","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1083\/jcb.201302044","volume":"201","author":"YR Li","year":"2013","unstructured":"Li, Y. R., King, O. D., Shorter, J. & Gitler, A. D. Stress granules as crucibles of ALS pathogenesis. J Cell Biol \n                           201, 361\u2013372 (2013).","journal-title":"J Cell Biol"},{"key":"14966_CR6","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/nn.2778","volume":"14","author":"JR Tollervey","year":"2011","unstructured":"Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci \n                           14, 452\u2013458 (2011).","journal-title":"Nat Neurosci"},{"key":"14966_CR7","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1038\/nn.3230","volume":"15","author":"C Lagier-Tourenne","year":"2012","unstructured":"Lagier-Tourenne, C. et al. Divergent roles of ALS-linked proteins FUS\/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci \n                           15, 1488\u20131497 (2012).","journal-title":"Nat Neurosci"},{"key":"14966_CR8","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1093\/emboj\/20.7.1774","volume":"20","author":"E Buratti","year":"2001","unstructured":"Buratti, E. et al. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J \n                           20, 1774\u20131784 (2001).","journal-title":"EMBO J"},{"key":"14966_CR9","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/emboj.2010.310","volume":"30","author":"YM Ayala","year":"2011","unstructured":"Ayala, Y. M. et al. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J \n                           30, 277\u2013288 (2011).","journal-title":"EMBO J"},{"key":"14966_CR10","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1126\/science.1154584","volume":"319","author":"J Sreedharan","year":"2008","unstructured":"Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science \n                           319, 1668\u20131672 (2008).","journal-title":"Science"},{"key":"14966_CR11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrn3121","volume":"13","author":"EB Lee","year":"2011","unstructured":"Lee, E. B., Lee, V. M. & Trojanowski, J. Q. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. 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Proc Natl Acad Sci USA \n                           107, 3858\u20133863 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"14966_CR18","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1093\/brain\/awr159","volume":"134","author":"V Swarup","year":"2011","unstructured":"Swarup, V. et al. Pathological hallmarks of amyotrophic lateral sclerosis\/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain \n                           134, 2610\u20132626 (2011).","journal-title":"Brain"},{"key":"14966_CR19","doi-asserted-by":"publisher","first-page":"8516","DOI":"10.1074\/jbc.M809462200","volume":"284","author":"LM Igaz","year":"2009","unstructured":"Igaz, L. M. et al. Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. 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Genes Cells \n                           16, 479\u2013490 (2011).","journal-title":"Genes Cells"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14966-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14966-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14966-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T13:07:27Z","timestamp":1671800847000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14966-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,2]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["14966"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-14966-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,2]]},"assertion":[{"value":"23 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14972"}}