G-quadruplex poses quadruple threat

Abstract

Multiplication of repetitive DNA sequences is often the cause of neurodegenerative diseases. A four-stranded structure has been found to form in one such expansion in the gene C9orf72, altering gene function in four ways. See Article p.195 Repeat expansions — mutations in which extra copies of tandemly repeated DNA sequence are generated — underlie more than 40 genetic diseases, which typically lead to neurological and neuromuscular problems. The C9orf72 hexanucleotide repeat expansion has been identified as a cause for both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Normal C9orf72 contains up to 25 repeats, whereas those in afflicted individuals can have thousands. This study suggests that a gain in RNA toxicity underlies C9orf72-linked pathology in ALS/FTD. Transcribed C9orf72 hexanucleotide repeats are shown to bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner; as a result nucleolin is mislocalized and functionally impaired, leading to nucleolar stress.