There has been accumulating evidence over the last decade that the etiology of amyotrophic lateral sclerosis (ALS) involves alterations in RNA processing and metabolism. Recently, a mutation that consists of the expansion of a hexanucleotide repeat in the C9orf72 gene was found in ALS families (c9ALS). The abnormal repeat leads to the accumulation of C9orf72 transcripts and the generation of dipeptide-repeat protein (DPRs), both of which are thought to be neurotoxic. Interestingly, many RNA-binding proteins form aggregates in c9ALS, and DPRs are thought to affect RNA biogenesis. These findings suggest that RNA metabolism could be affected on a large scale in the disease, but the extent of such changes is currently unknown.

On page 1175 of this issue, Petrucelli and colleagues report their analysis of brain transcriptomes in c9ALS and sporadic ALS (sALS) patients. Using RNA sequencing on cerebellar and frontal cortex samples, the authors found hundreds of genes that were differentially expressed in patients and healthy individuals. Twice as many genes were dysregulated in c9ALS than in sALS, but, surprisingly, only a small fraction of changes occurred in the same genes in the two patient groups. The authors also identified distinct coexpression network modules in c9ALS and sALS and found that alternative splicing (AS) and alternative polyadenylation were higher in c9ALS than in sALS samples, with only a small fraction of AS events shared across the two groups. The picture shows hierarchical clustering of individuals based on the pattern of differentially expressed genes in frontal cortex (red and blue tick marks in the square indicate up- and downregulated genes, respectively). The bar on the left shows individual controls in white, sALS cases in purple and c9ALS cases in black. Note the segregation of the two patient populations into distinct clusters, pointing to the transcriptomic divergence between c9ALS and sALS.

This exploratory analysis of the transcriptional landscape in ALS reveals widespread changes in RNA expression and processing and further anchors the RNA-centric view of ALS. However, the modest overlap in the changes in RNA expression and processing between c9LAS and sALS suggests an important divergence in the molecular presentation of the disease in these two patient populations and possibly predicts a more general heterogeneity of the disease. Although it is currently unclear which of these RNA changes relate to the neuropathology of the disease or how, this study represents an important step in our understanding of the molecular etiology of ALS. Public access to these data will hopefully seed many future mechanistic studies that will bridge the genetics of the disease to the biology underlying its pathogenesis.