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Mori, K.* ; Arzberger, T.* ; Grässer, F.A.* ; Gijselinck, I.* ; May, S.* ; Rentzsch, K.* ; Weng, S.M.* ; Schludi, M.H.* ; van der Zee, J.* ; Cruts, M.* ; van Broeckhoven, C.* ; Kremmer, E. ; Kretzschmar, H.A.* ; Haass, C.* ; Edbauer, D.*

Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins.

Acta Neuropathol. 126, 881-893 (2013)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Neurodegeneration ; C9orf72 ; Ftld ; Als ; Ran Translation; Frontotemporal Lobar Degeneration ; Amyotrophic-lateral-sclerosis ; Tdp-43-negative Inclusions ; Molecular-basis ; Ggggcc Repeat ; Expansion ; Dementia ; Spectrum ; Als ; Tdp-43
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Zeitschrift Acta Neuropathologica
Quellenangaben Band: 126, Heft: 6, Seiten: 881-893 Artikelnummer: , Supplement: ,
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501793-001
PubMed ID 24132570
DOI 10.1007/s00401-013-1189-3
WOS ID WOS:000327100500008
Scopus ID 84892585689
Erfassungsdatum 2013-12-13
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