TY - JOUR TI - Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism AU - Conlon, Erin G AU - Fagegaltier, Delphine AU - Agius, Phaedra AU - Davis-Porada, Julia AU - Gregory, James AU - Hubbard, Isabel AU - Kang, Kristy AU - Kim, Duyang AU - The New York Genome Center ALS Consortium AU - Phatnani, Hemali AU - Shneider, Neil A AU - Manley, James L VL - 7 PY - 2018 DA - 2018/07/13 SP - e37754 C1 - eLife 2018;7:e37754 DO - 10.7554/eLife.37754 UR - https://doi.org/10.7554/eLife.37754 AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum. KW - amyotrophic lateral aclerosis KW - frontotemporal dementia KW - mRNA splicing KW - RNA binding proteins JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -