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.

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Abnormal proteins in the CNS of individuals with ALS causative mutations may provide specific biomarkers in gene-targeted therapy. Repeat expansions in C9ORF72, called dipeptide repeat proteins, in patients with ALS are presumably generated by non-ATG translation, serve as a critical component of p62 positive inclusions found in the cerebellum and hippocampus, and can also be identified in CSF [44][45][46]. The specificity of dipeptide repeat proteins for these patients confers an opportunity for use in trials and could even be a therapeutic target [47].…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…The C9orf72 hexanucleotide G 4 C 2 repeat is located within the first intron of the locus, in a noncoding region, and yet is translated into polypeptides through a unique pathway known as repeat-associated non-AUG dependent (RAN) translation [130][131][132][133] (Fig. 1).…”

Toxic RNA as a driver of disease in a common form of ALS and dementia

“…One needs to remain open to the idea that expanded repeats so much longer than 30 GGGGCCs either might not sequester RNA-binding proteins and/or trigger another mechanism such as gene silencing at the C9ORF72 locus or translation of a toxic peptide. In this regard, it is worth noting that two groups recently reported immunostaining for GGGGCC repeat encoded insoluble peptides in the brains of patients who succumbed to C9ORF72 disease (9,10). Whether these peptides actually contribute to C9ORF72 remains to be shown.…”