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This repeat is thought to elicit toxicity through RNA mediated protein sequestration and repeat-associated non-AUG (RAN) translation of dipeptide repeat proteins (DPRs). We generated a series of transgenic\n                    <jats:italic>Drosophila<\/jats:italic>\n                    models expressing GGGGCC (G\n                    <jats:sub>4<\/jats:sub>\n                    C\n                    <jats:sub>2<\/jats:sub>\n                    ) repeats either inside of an artificial intron within a GFP reporter or within the 5\u2032 untranslated region (UTR) of GFP placed in different downstream reading frames. Expression of 484 intronic repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of repeats into the 5\u2032 UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus (C-terminus) in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR C-terminus was observed when repeats were expressed in rodent neurons. The presence of the native C-termini across all three reading frames was partly protective. Taken together, these findings suggest that C-terminal sequences outside of the repeat region may alter the behavior and toxicity of dipeptide repeat proteins derived from GGGGCC repeats.\n                  <\/jats:p>","DOI":"10.1186\/s40478-020-01002-8","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T04:02:59Z","timestamp":1596513779000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS\/FTD"],"prefix":"10.1186","volume":"8","author":[{"given":"Fang","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany N.","family":"Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Krans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Frazer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Natla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarjina","family":"Niraula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olamide","family":"Adefioye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami J.","family":"Barmada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4781-6376","authenticated-orcid":false,"given":"Peter K.","family":"Todd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,4]]},"reference":[{"key":"1002_CR1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/ana.21948","volume":"67","author":"PK Todd","year":"2010","unstructured":"Todd PK, Paulson HL (2010) RNA-mediated neurodegeneration in repeat expansion disorders. 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