{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:11:05Z","timestamp":1791288665389,"version":"4.3.0"},"reference-count":55,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,8,25]],"date-time":"2017-08-25T00:00:00Z","timestamp":1503619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100008027","name":"Accademia Nazionale dei Lincei","doi-asserted-by":"publisher","award":["47\/2014\/A"],"award-info":[{"award-number":["47\/2014\/A"]}],"id":[{"id":"10.13039\/501100008027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005247","name":"University of British Columbia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005247","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin\u2010positive inclusions are neurodegenerative disorders that share the cytosolic deposition of TDP\u201043 (TAR DNA\u2010binding protein 43) in the CNS. TDP\u201043 is well known as being actively degraded by both the proteasome and macroautophagy. The well\u2010documented decrease in the efficiency of these clearance systems in aging and neurodegeneration, as well as the genetic evidence that many of the familial forms of TDP\u201043 proteinopathies involve genes that are associated with them, suggest that a failure of these protein degradation systems is a major factor that contributes to the onset of TDP\u201043\u2013associated disorders. Here, we inserted preformed human TDP\u201043 aggregates in the cytosol of murine NSC34 and N2a cells in diffuse form and observed their degradation under conditions in which exogenous TDP\u201043 is not expressed and endogenous nuclear TDP\u201043 is not recruited, thereby allowing a time zero to be established in TDP\u201043 degradation and to observe its disposal kinetically and analytically. TDP\u201043 degradation was observed in the absence and presence of selective inhibitors and small interfering RNAs against the proteasome and autophagy. We found that cytosolic diffuse aggregates of TDP\u201043 can be distinguished in 3 different classes on the basis of their vulnerability to degradation, which contributed to the definition\u2014with previous reports\u2014of a total of 6 distinct classes of misfolded TDP\u201043 species that range from soluble monomer to undegradable macroaggregates. We also found that the proteasome and macroautophagy\u2010degradable pools of TDP\u201043 are fully distinguishable, rather than in equilibrium between them on the time scale required for degradation, and that a significant crosstalk exists between the 2 degradation processes.\u2014Cascella, R., Fani, G., Capitini, C., Rusmini, P., Poletti, A., Cecchi, C., Chiti, F. Quantitative assessment of the degradation of aggregated TDP\u201043 mediated by the ubiquitin proteasome system and macroautophagy. FASEB J. 31, 5609\u20135624 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700292rr","type":"journal-article","created":{"date-parts":[[2017,8,25]],"date-time":"2017-08-25T20:11:18Z","timestamp":1503691878000},"page":"5609-5624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Quantitative assessment of the degradation of aggregated TDP\u201043 mediated by the ubiquitin proteasome system and macroautophagy"],"prefix":"10.1096","volume":"31","author":[{"given":"Roberta","family":"Cascella","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Fani","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Capitini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Rusmini","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari Centro di Eccellenza sulle Malattie Neurodegenerative Universita degli Studi di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Poletti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmacologiche e Biomolecolari Centro di Eccellenza sulle Malattie Neurodegenerative Universita degli Studi di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Cecchi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Chiti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,8,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21147"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105313442207"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-4-3"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-014-0489-x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086720"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.737726"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.038950"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.012195"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08256.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3121"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1030-4"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800342200"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp275"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200908115"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22243"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq257"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2009.11.055"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-5-33"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.136150"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.140087"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2014.00070"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5802"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2404-2_3"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.03.032"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv193"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10353"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.11.036"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.250"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000231510.89311.8b"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08971"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.12.010"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-160"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-166"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001940306"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1515\/hsz-2015-0250"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32721"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.310"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10098"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11468"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.278"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1308985"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.04.007"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00177"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-011-0795-6"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2010.203"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00176"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022850"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds321"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw232"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.417600"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5050"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.25573"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2014.02.056"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0315-5"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201700292RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201700292RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201700292RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:49:59Z","timestamp":1761666599000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201700292RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,25]]},"references-count":55,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1096\/fj.201700292RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.201700292rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,25]]},"assertion":[{"value":"2017-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}