Conlon, E. G., Fagegaltier, D., Agius, P., Davis-Porada, J., Gregory, J., Hubbard, I., Kang, K., Kim, D., Phatnani, H., Shneider, N. A., Manley, J. L., Kwan, J., Sareen, D., Broach, J. R., Simmons, Z., Arcila-Londono, X., Lee, E. B., Van Deerlin, V. M., Fraenkel, E., Ostrow, L. W., Baas, F., Zaitlen, N., Berry, J. D., Malaspina, A., Fratta, P., Cox, G. A., Thompson, L. M., Finkbeiner, S., Dardiotis, E., Miller, T. M., Chandran, S., Pal, S., Hornstein, E., Macgowan, D. J., Heiman-Patterson, T., Hammell, M. G., Patsopoulos, N. A., Dubnau, J., Nath, A., Phatnani, H., Shneider, N. A., Manley, J. L. (July 2018) Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism. eLife, 7. ISSN 2050084X (ISSN)
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Abstract
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. © 2018, eLife Sciences Publications Ltd. All rights reserved.
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