TY  - JOUR
AU  - Mori, Kohji
AU  - Arzberger, Thomas
AU  - Grässer, Friedrich A
AU  - Gijselinck, Ilse
AU  - May, Stephanie
AU  - Rentzsch, Kristin
AU  - Weng, Shih-Ming
AU  - Schludi, Martin H
AU  - van der Zee, Julie
AU  - Cruts, Marc
AU  - Van Broeckhoven, Christine
AU  - Kremmer, Elisabeth
AU  - Kretzschmar, Hans A
AU  - Haass, Christian
AU  - Edbauer, Dieter
TI  - Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins.
JO  - Acta neuropathologica
VL  - 126
IS  - 6
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-03448
SP  - 881-893
PY  - 2013
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: diagnosis
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Brain: metabolism
KW  - C9orf72 Protein
KW  - DNA Repeat Expansion
KW  - Frontotemporal Lobar Degeneration: diagnosis
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Humans
KW  - Protein Biosynthesis
KW  - Proteins: genetics
KW  - Proteins: metabolism
KW  - C9orf72 Protein (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24132570
DO  - DOI:10.1007/s00401-013-1189-3
UR  - https://pub.dzne.de/record/137126
ER  -