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)
|
PDF
Conlon_eLife_2018.pdf - Published Version Download (6MB) | Preview |
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing |
| CSHL Authors: | |
| Communities: | CSHL labs > Hammell M. lab |
| Depositing User: | Matthew Dunn |
| Date: | 13 July 2018 |
| Date Deposited: | 06 Sep 2018 19:08 |
| Last Modified: | 01 Oct 2019 19:34 |
| PMCID: | PMC6103746 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/37191 |
Actions (login required)
 |
Administrator's edit/view item |
