{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:15:47Z","timestamp":1787008547488,"version":"build-2736575974"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000124","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000124","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004897","name":"Pennsylvania Department of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein quality control pathways have evolved to ensure the fidelity of protein synthesis and efficiently clear potentially toxic protein species. Defects in ribosome-associated quality control and its associated factors have been implicated in the accumulation of aberrant proteins and neurodegeneration. C9orf72 repeat-associated non-AUG translation has been suggested to involve inefficient translation elongation, lead to ribosomal pausing and activation of ribosome-associated quality control pathways. However, the role of the ribosome-associated quality control complex in the processing of proteins generated through this non-canonical translation is not well understood. Here we use reporter constructs containing the C9orf72-associated hexanucleotide repeat, ribosome-associated quality control complex deficient cell models and stain for ribosome-associated quality control markers in C9orf72-expansion carrier human tissue to understand its role in dipeptide-repeat protein pathology.<\/jats:p>\n                  <jats:p>Our studies show that canonical ribosome-associated quality control substrates products are efficiently cleared by the ribosome-associated quality control complex in mammalian cells. Furthermore, using stalling reporter constructs, we show that repeats associated with the C9orf72-expansion induce ribosomal stalling when arginine (R)-rich dipeptide-repeat proteins are synthesized in a length-dependent manner. However, despite triggering this pathway, these arginine-rich dipeptide-repeat proteins are not efficiently processed by the core components of the ribosome-associated quality control complex (listerin, nuclear-export mediator factor and valosin containing protein) partly due to lack of lysine residues, which precludes ubiquitination. Deficient processing by this complex may be implicated in C9orf72-expansion associated disease as dipeptide-repeat protein inclusions were observed to be predominantly devoid of ubiquitin and co-localize with nuclear-export mediator factor in mutation carriers\u2019 frontal cortex and cerebellum tissue. These findings suggest that impaired processing of these arginine-rich dipeptide-repeat proteins derived from repeat-associated non-AUG translation by the ribosome-associated quality control complex may contribute to protein homeostasis dysregulation observed in C9orf72-expansion amyotrophic lateral sclerosis and frontotemporal degeneration neuropathogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awac479","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T09:46:17Z","timestamp":1670924777000},"page":"2897-2912","source":"Crossref","is-referenced-by-count":20,"title":["Impaired ribosome-associated quality control of\n                    <i>C9orf72<\/i>\n                    arginine-rich dipeptide-repeat proteins"],"prefix":"10.1093","volume":"146","author":[{"given":"Ashley P","family":"Viera Ortiz","sequence":"first","affiliation":[{"name":"Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"},{"name":"Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Cajka","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"},{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olamide A","family":"Olatunji","sequence":"additional","affiliation":[{"name":"Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Mikytuck","sequence":"additional","affiliation":[{"name":"Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ophir","family":"Shalem","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"},{"name":"Department of Genetics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-1180","authenticated-orcid":false,"given":"Edward B","family":"Lee","sequence":"additional","affiliation":[{"name":"Translational Neuropathology Research Laboratory, Department 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