Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
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 post-mortem 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.
Elife. 2018 Jul 13;7. pii: e37754. doi: 10.7554/eLife.37754. [Epub ahead of print]
Conlon EG1, Fagegaltier D2, Agius P2, Davis-Porada J1, Gregory J2, Hubbard I2, Kang K2, Kim D2; New York Genome Center ALS Consortium, Phatnani H3, Shneider NA4, Manley JL1.
1 Department of Biological Sciences, Columbia University, New York, United States.
2 Center for Genomics of Neurodegenerative disease, New York Genome Center, New York, United States.
3 Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, United States.
4 Department of Neurology, Columbia University, New York, United States.