The most common cause of the debilitating disease amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion GGGGCC (G4C2) in the C9orf72 gene. Two studies in this issue use contrasting methods to arrive at a molecular mechanism that may cause a familial form of the disease. Using a candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats (Ke Zhang et al.) or an unbiased genetic screen in Drosophila expressing 8, 28 or 58 G4C2 repeat-containing transcripts (Brian Freibaum et al.), the two groups sought genes that enhance or suppress the disease phenotype. Zhang et al. identify the gene encoding RanGAP, a key regulator of nucleocytoplasmic transport, and Freibaum et al. identifies genes that encode components of the nuclear pore and the nucleocytoplasmic transport machinery. Both papers show deficits in nucleocytoplasmic transport in Drosophila cells expressing G4C2 repeats and in iPSC-derived neurons from ALS patients. Zhang et al. show that these defects can be rescued with antisense oligonucleotides or small molecules targeting the G-quadruplexes.
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