Pathogenic Mechanisms and Therapy Development for C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Abstract

In 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of evidence favors gain of toxicity as the main pathogenic mechanism for C9orf72 repeat expansions. Alterations in several downstream cellular functions, such as nucleocytoplasmic transport and autophagy, are implicated. Exciting progress has also been made in therapy development targeting this mutation, such as by antisense oligonucleotide therapies targeting sense transcripts and small molecules targeting nucleocytoplasmic transport, and these are now in phase 1 clinical trials.

Keywords: C9orf72; RNA foci; amyotrophic lateral sclerosis; antisense oligonucleotide; dipeptide repeat proteins; frontotemporal dementia; nucleocytoplasmic transport.

Fig. 1

C9orf72 gene structure, RNA transcripts, and proteins. (a) Schematic representation of the human C9orf72 gene with expanded GGGGCC hexanucleotide repeats. (b) Three RNA transcripts can be produced from the C9orf72 gene. Variant 1 is predicted to result in a “short isoform” C9ORF72 protein of 222 amino acids, whereas variants 2 and 3 encode a long C9ORF72 protein of 481 amino acids

Fig. 2

Proposed pathogenic mechanisms in C9orf72 ALS/FTD. (a) The presence of expanded GGGGCC repeats potentially causes abortive transcription from exon 1a and hypermethylation of both DNA and histones to reduce C9orf72 RNA transcription, leading to a loss of C9orf72 protein function. (b) Bidirectionally transcribed repeat-containing RNAs cause neuronal toxicity by sequestration of RNA-binding proteins into RNA foci or production of at least 5 aberrant dipeptide repeat proteins [poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA)] through a novel repeat-associated non-AUG-dependent translation mechanism

Fig. 3

Cellular processes impaired by the C9orf72 repeat expansions and potential therapeutic interventions. A wide range of cellular pathways have been implicated in c9ALS/FTD, including DNA damage, nucleolar stress, nucleocytoplasmic transport deficits, ER stress, autophagy dysfunction, translational inhibition, proteasome inhibition, and altered stress granule dynamics. Therapies targeting these deficits, as well as directly targeting repeat expanded C9orf72 DNA/RNA and DPR proteins, are also highlighted