title: The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.
abstract: Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.
authors: Adolf Butenandt-Institute, Biochemistry, Ludwig-Maximilians University (LMU) Munich, Munich, Germany.
authors: Kohji
authors: K
authors: Mori
authors: Shih-Ming
authors: SM
authors: Weng
authors: Thomas
authors: T
authors: Arzberger
authors: Stephanie
authors: S
authors: May
authors: Kristin
authors: K
authors: Rentzsch
authors: Elisabeth
authors: E
authors: Kremmer
authors: Bettina
authors: B
authors: Schmid
authors: Hans A
authors: HA
authors: Kretzschmar
authors: Marc
authors: M
authors: Cruts
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Christian
authors: C
authors: Haass
authors: Dieter
authors: D
authors: Edbauer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016366:Open Reading Frames; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein