Home > Publications Database > Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. > print

001     137126
005     20250321142424.0
024 7 _ |a 10.1007/s00401-013-1189-3
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024 7 _ |a pmid:24132570
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024 7 _ |a 0001-6322
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024 7 _ |a 1432-0533
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024 7 _ |a altmetric:32580480
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037 _ _ |a DZNE-2020-03448
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Mori, Kohji
|b 0
245 _ _ |a Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins.
260 _ _ |a Heidelberg
|c 2013
|b Springer
264 _ 1 |3 online
|2 Crossref
|b Springer Science and Business Media LLC
|c 2013-10-17
264 _ 1 |3 print
|2 Crossref
|b Springer Science and Business Media LLC
|c 2013-12-01
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a Massive GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most common known cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Despite its intronic localization and lack of an ATG start codon, the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg). We took an antibody-based approach to further validate the translation of DPR proteins. To test whether the antisense repeat RNA transcript is also translated, we raised antibodies against the predicted products, poly-(Ala-Pro) and poly-(Pro-Arg). Both antibodies stained p62-positive neuronal cytoplasmic inclusions throughout the cerebellum and hippocampus indicating that not only sense but also antisense strand repeats are translated into DPR proteins in the absence of ATG start codons. Protein products of both strands co-aggregate suggesting concurrent translation of both strands. Moreover, an antibody targeting the putative carboxyl terminus of DPR proteins can detect inclusion pathology in C9orf72 repeat expansion carriers suggesting that the non-ATG translation continues through the entire repeat and beyond. A highly sensitive monoclonal antibody against poly-(Gly-Arg), visualized abundant inclusion pathology in all cortical regions and some inclusions also in motoneurons. Together, our data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion. Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS.
536 _ _ |a 342 - Disease Mechanisms and Model Systems (POF3-342)
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542 _ _ |i 2013-10-17
|2 Crossref
|u http://www.springer.com/tdm
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a C9orf72 Protein
|2 NLM Chemicals
650 _ 7 |a C9orf72 protein, human
|2 NLM Chemicals
650 _ 7 |a Proteins
|2 NLM Chemicals
650 _ 2 |a Amyotrophic Lateral Sclerosis: diagnosis
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a C9orf72 Protein
|2 MeSH
650 _ 2 |a DNA Repeat Expansion
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: diagnosis
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: genetics
|2 MeSH
650 _ 2 |a Frontotemporal Lobar Degeneration: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Protein Biosynthesis
|2 MeSH
650 _ 2 |a Proteins: genetics
|2 MeSH
650 _ 2 |a Proteins: metabolism
|2 MeSH
700 1 _ |a Arzberger, Thomas
|0 P:(DE-2719)2811333
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700 1 _ |a Grässer, Friedrich A
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700 1 _ |a Gijselinck, Ilse
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700 1 _ |a May, Stephanie
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700 1 _ |a Rentzsch, Kristin
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700 1 _ |a Weng, Shih-Ming
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700 1 _ |a Schludi, Martin H
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700 1 _ |a van der Zee, Julie
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700 1 _ |a Cruts, Marc
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700 1 _ |a Van Broeckhoven, Christine
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700 1 _ |a Kremmer, Elisabeth
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700 1 _ |a Kretzschmar, Hans A
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700 1 _ |a Haass, Christian
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700 1 _ |a Edbauer, Dieter
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773 1 8 |a 10.1007/s00401-013-1189-3
|b : Springer Science and Business Media LLC, 2013-10-17
|n 6
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|t Acta Neuropathologica
|v 126
|y 2013
|x 0001-6322
773 _ _ |a 10.1007/s00401-013-1189-3
|g Vol. 126, no. 6, p. 881 - 893
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|q 126:6<881 - 893
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|t Acta neuropathologica
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856 4 _ |u https://pub.dzne.de/record/137126/files/DZNE-2020-03448_Restricted.pdf
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