A novel mechanism of neurodegeneration

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.