The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS

By K. Mori, S. Weng, T. Arzberger, S. May, K. Rentzsch, E. Kremmer, Bettina Schmid, H. Kretzschmar, M. Cruts, C. van Broeckhoven and 2 more. Science, 2013

1,262 citations recorded by the source corpus.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/2726c34cddec259bb3f2e10e6364ab907746a600

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In Neurology

Citations in the corpus

Hallmarks of neurodegenerative diseases. (2023, neutral): “28,44,53,54,56,57,65 Mislocalized TDP-43, which functions as an RNA-binding protein, causes altered RNA splicing, RNA stability, and RNA transport.”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, positive): “While two RNA-binding proteins, hnRNP-A3 (Mori et al., 2013a) and Pur-a (Xu et al., 2013), have been reported to bind GGGGCC repeats in vitro and both were reported to be components of p62-positive TDP-43-negative inclusions in C9ORF72 patients, their role in pathogenesis is unproven.”
Targeting RNA foci in iPSC-derived motor neurons from ALS patients with C9ORF72 repeat expansion (2013, background): “Some noncoding repeats including those in DM1 and SCA8 were shown to produce non-ATG– initiated peptides, which could also play a role in disease pathogenesis (43); similarly generated peptides were recently demonstrated in C9-ALS patient tissue (16, 17).”
RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention (2013, positive): “…pulldown assays with different sources of cell lysates, such as human kidney cell lysates and mouse CNS lysates, have identified commonly known RBPs such as hnRNP (e.g., hnRNPA3) proteins and Pur a as interactors to the GGGGCC exp repeat (Xu et al., 2013; Mori et al., 2013a; Almeida et al., 2013).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “Toxic repeat proteins, such as polyQ and additional homopolymeric expansion proteins in HD (14) or dipeptide repeat (DPR) proteins, e.g., polyGR and polyPR, in C9ORF72-linked ALS/FTD (11, 110), may also contribute to disease by aberrant phase separation.”
C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins (2014, background): “The GGGGCC repeat can be translated in all sense and antisense frames, two of which encode the same DPR, resulting in five DPR proteins, all of which form inclusions in widespread brain regions (10, 12, 14-18).”
RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia (2013, background): “Moving forward, it will be important to examine the role that sense and antisense transcripts, their respective binding proteins, as well as any potential interactions between these factors, might play in C9ORF72 ALS/FTD.”