The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease

Key Points Since its discovery as the most common genetic abnormality in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), researchers have sought to understand the pathophysiology that results from the chromosome 9 open reading frame 72 ( C9orf72 ) hexanucleotide expansion. Several pathways have been proposed to contribute. The nucleotide expansion may disrupt transcription, promoter activation and epigenetic regulation and may therefore drive a loss of C9orf72 function. A body of evidence suggests that cellular dysfunction results from toxicity that occurs downstream of the nucleotide repeat. There are several types of pathology associated with the nucleotide expansion that may drive this toxicity, including RNA foci, dipeptide repeat aggregates and nuclear pathology. Nucleocytoplasmic transport defects are a key contributor to C9orf72-driven pathophysiology. Studies of human brains, induced pluripotent stem cell-derived neurons, flies and yeast models, converge to suggest that nuclear export and import are defective in cells carrying the mutation. Several therapeutic strategies are being explored. For example, antisense oligonucleotides and small molecules may mitigate toxicity caused by the C9orf72 nucleotide repeat expansion. A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 ( C9orf72 ) gene is linked to multiple neurological conditions. Rothstein and colleagues evaluate the evidence indicating that the NRE causes a loss of C9orf72 function or drives toxic gain-of-function mechanisms and consider the cellular defects through which the mutation drives disease pathology. A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 ( C9orf72 ) gene was the first of this type of mutation to be linked to multiple neurological conditions, including amyotrophic lateral sclerosis and frontotemporal dementia. The pathogenic mechanisms through which the C9orf72 NRE contributes to these disorders include loss of C9orf72 function and gain-of-function mechanisms of C9orf72 driven by toxic RNA and protein species encoded by the NRE. These mechanisms have been linked to several cellular defects — including nucleocytoplasmic trafficking deficits and nuclear stress — that have been observed in both patients and animal models.