Bidirectional Transcriptional Inhibition as Therapy for ALS/FTD Caused by Repeat Expansion in C9orf72  Jie Jiang, Don W. Cleveland  Neuron  Volume 92, Issue 6, Pages 1160-1163 (December 2016) DOI: 10.1016/j.neuron.2016.12.008 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Proposed Disease Mechanisms Caused by C9orf72 GGGGCC Repeat Expansions and Therapy Development (A) Schematic representation of the human C9orf72 gene. GGGGCC hexanucleotide repeat expansion is located between alternative exons 1a and 1b. (B and C) C9orf72 repeat expansions are proposed to lead ALS/FTD through either (B) inhibition of C9orf72 transcription and thus loss of protein function, and/or through (C) gain of toxicity from repeat containing RNAs. Both sense GGGGCC and antisense CCCCGG repeat-containing RNAs are transcribed from the mutant C9orf72 gene, form independent sense and antisense RNA foci to sequester key RNA-binding proteins and produce five different dipeptide repeat proteins through repeat-associated non-AUG-dependent (RAN) translation. Transcription elongation factor SUPT4H1, together with its binding partner SUPT5H, regulates transcription of both sense and antisense repeat expanded RNAs. Antisense oligonucleotides (ASOs) targeting SUPT4H1 or SUPT5H can bi-directionally suppress C9orf72 RNA transcription. Alternatively, ASOs can specifically target degradation of sense or antisense repeat-containing RNAs. Neuron 2016 92, 1160-1163DOI: (10.1016/j.neuron.2016.12.008) Copyright © 2016 Elsevier Inc. Terms and Conditions