Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that have been linked to a repeat expansion of the hexanucleotide sequence GGGGCC in C9ORF72. RNA transcribed from this repeat forms aggregates in the nucleus of neurons that can sequester key RNA-binding proteins. Non-ATG translation from the hexanucleotide sequence also occurs, leading to the formation of potentially toxic peptide aggregates within neurons. Both of these mechanisms could contribute to disease pathogenesis. Zhaoming Su et al. now report their development of small molecules that bind to RNA transcribed from this sequence, which could protect vulnerable neuronal populations (Neuron 83, 1043–1050, 2014).

By studying the structure that the hexanucleotide RNA adopts, the researchers generated small molecules that bind the transcript. These compounds reduce formation of RNA aggregates and peptides in neurons derived from fibroblasts of human carriers of the repeat expansion. In addition, Su et al. developed an immunoassay that enabled detection of these peptides in the cerebrospinal fluid (CSF) of individuals with ALS carrying the repeat expansion. This suggests that peptide levels in the CSF could serve as a biomarker for therapeutic response to the compounds they identified.