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A recent and very stimulating finding in the field of neurodegenerative disease is the discovery that expansion of a hexanucleotide microsatellite DNA repeat (GGGGCC) in an intron of the C90RF72 gene is a common cause of two devastating neurodegenerative diseases for which there are no cures: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (1, 2). With this observation arose a fascinating question—how does expansion of this repeat induce a disease that can manifest as ALS, a motor neuron disease, as well as FTD, a leading cause of presenile dementia? Adding to the mystery is the almost complete absence of information on the C9ORF72 gene or the function of the protein it encodes. However, initial characterization of C9ORF72-FTD/ALS combined with work on some other neurodegenerative diseases suggests three pathogenic mechanisms (Fig. 1). First is the evidence indicating that mRNA levels of C9ORF72 transcripts are decreased in C9ORF72-FTD/ALS (1⇓–3). Thus, a loss of C9ORF72 function might contribute to disease. Second, accumulation of RNA transcripts containing the GGGGCC repeat within nuclear foci in frontal cortex and spinal cord material in C9ORF72-FTD/ALS patients suggests a toxic RNA gain of function (1). This pathogenic mechanism is patterned after other noncoding expansion disorders where RNA foci lead to the sequestration and altered activity of RNA-binding proteins (4). A third possible pathogenic mechanism is repeat-associated non-ATG translation (RAN translation). RAN translation, a mode of translation that occurs in the absence of an initiating ATG codon, was first reported to occur across expanded CAG repeats to produce potentially toxic homopolymeric peptides (5). It is among these competing possibilities that now enters the work of Xu et al. in PNAS (6), showing that expression of the expanded C9ORF72 repeat is sufficient to cause neurodegeneration and that its ability to sequester the …

Toxic RNA as a driver of disease in a common form of ALS and dementia