Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a neurodegenerative disease that leads to paralysis and ultimately death in almost all cases. About 10% of cases are familial, and mutations in the gene C9ORF72 are to blame for about 40% of inherited cases. The function of C9ORF72 was unknown when it was discovered, but recently, three papers have identified a molecular mechanism that explains its role in causing ALS.

The three studies (Nature 525, 56–61 and 129–133; and Nat. Neurosci. 18, 1226–1229; 2015) used unbiased screens in Drosophila melanogaster and yeast to identify genes that interacted with C9ORF72 in causing ALS-related pathology. These screens consistently identified proteins that function to regulate the import of other proteins into the cell nucleus.

The C9ORF72 gene contains a section of DNA in which a six-nucleotide pattern repeats. “Healthy people have two to five repeats of this six-nucleotide pattern,” said Aaron Gitler (Stanford University, Palo Alto, CA), senior author on the paper in Nature Neuroscience, in a press release. “But in some people, this region is expanded into hundreds or thousands of copies.” To figure out how this repeat expansion leads to ALS pathology, the authors of the three studies engineered Drosophila or yeast expressing the expanded gene, which caused toxicity in yeast and fly cells, and locomotor deficits in fliesicits in flies. The researchers then screened hundreds of genes, seeking those that affect this toxicity.

In each study, the screens independently identified proteins involved in the import of nuclear proteins. Genes that increased nuclear import or suppressed nuclear export of proteins ameliorated neurodegeneration, whereas genes that interfered with nuclear import exacerbated it. These results were confirmed in neurons derived from patients that carry the C9ORF72 mutation. Postmortem brain tissue from ALS patients with the mutation also showed deficits in nuclear import of proteins. “Combining a simple fruit fly model with experiments in cells donated by ALS and [frontotemporal dementia] patients was essential for discovering the disease mechanism underlying mutations in C9ORF72,” said Paul Taylor (St. Jude Children's Research Hospital, Memphis, TN), senior author of one of the papers in Nature, in a press release. The other paper in Nature showed that a drug that interferes with the interaction between nuclear import proteins and RNA from repeat-expanded C9ORF72 positively affected pathology in Drosophila. “This is certainly a good therapeutic target,” said Jeff Rothstein (Johns Hopkins University Medical School, Baltimore, MD), the paper's senior author.