RNA-mediated toxicity in C9orf72 ALS and FTD

Abstract

A GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Compelling evidence suggests that gain of toxicity from the bidirectionally transcribed repeat expanded RNAs plays a central role in disease pathogenesis. Two potential mechanisms have been proposed including RNA-mediated toxicity and/or the production of toxic dipeptide repeat proteins. In this review, we focus on the role of RNA mediated toxicity in ALS/FTD caused by the C9orf72 mutation and discuss arguments for and against this mechanism. In addition, we summarize how G₄C₂ repeat RNAs can elicit toxicity and potential therapeutic strategies to mitigate RNA-mediated toxicity.

Keywords: Amyotrophic lateral sclerosis; Antisense oligonucleotide; C9orf72; Dipeptide repeat proteins; Frontotemporal dementia; RNA foci; RNA-mediated toxicity.

Figure 1.. C9orf72 gene structure.

A) Schematic of the C9orf72 gene with expanded G₄C₂ repeats in intron 1. B) Three RNA transcript variants are transcribed from the C9orf72 gene. Variant 1 encodes a predicted short isoform protein composed of only 222 amino acids. Variant 2 and variant 3 encode the full-length isoform composed of 481 amino acids. While variant 2 and 3 encode the same isoform, they are transcribed from different transcriptional start sites.

Figure 2.. Putative disease mechanisms in c9ALS/FTD.

Putative disease mechanisms in c9ALS/FTD include 1) haploinsuffiency of C9orf72, 2) gain of toxicity from the bidirectionally transcribed RNAs mediated through RNA-mediated toxicity via sequestration of RNA binding proteins, and/or production of five aberrant dipeptide repeats (GA, GP, GR, PR, PA) through repeat associated non-AUG dependent translation. Adapted from (Gitler and Tsuiji, 2016)