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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,10,5]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    The G\n                    <jats:sub>4<\/jats:sub>\n                    C\n                    <jats:sub>2<\/jats:sub>\n                    repeat expansion in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene is a major cause of frontotemporal dementia and amyotrophic lateral sclerosis. Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins (DPRs), PR\n                    <jats:sub>X<\/jats:sub>\n                    and GR\n                    <jats:sub>X<\/jats:sub>\n                    , which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in both\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    and mammalian neurons depends on the E3 ubiquitin ligase adaptor\n                    <jats:italic>SPOP<\/jats:italic>\n                    .\n                    <jats:italic>SPOP<\/jats:italic>\n                    acts through bromodomain proteins to mediate dipeptide toxicity.\n                    <jats:italic>SPOP<\/jats:italic>\n                    inhibitors, which are currently being developed to treat\n                    <jats:italic>SPOP<\/jats:italic>\n                    -dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and \u201cdruggable\u201d pathway that may represent a strategy for treating these currently incurable diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2104664118","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T17:36:15Z","timestamp":1633023375000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity"],"prefix":"10.1073","volume":"118","author":[{"given":"Carley","family":"Snoznik","sequence":"first","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Medvedeva","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4187-7207","authenticated-orcid":false,"given":"Jelena","family":"Mojsilovic-Petrovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Rudich","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224;"},{"name":"Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8688-9159","authenticated-orcid":false,"given":"James","family":"Oosten","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Kalb","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-9075","authenticated-orcid":false,"given":"Todd","family":"Lamitina","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224;"},{"name":"Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261;"},{"name":"Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.010"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70261-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0047-2"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.033"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315438110"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-2-70"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.010"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256800"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4085"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14973"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14974"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0071-1"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.12.030"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0249-16.2017"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.056"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0397-0"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.02.013"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.002"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0070-7"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx372"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep20877"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.003"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0146-8"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx309"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx170"},{"key":"e_1_3_4_27_2","first-page":"704","article-title":"SPOP 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