Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism

作者：Conlon Erin G; Fagegaltier Delphine; Agius Phaedra; Davis Porada Julia; Gregory James; Hubbard Isabel; Kang Kristy; Kim Duyang; Phatnani Hemali; Shneider Neil A; Manley James L^*

来源：eLife, 2018, 7: e37754.

DOI：10.7554/eLife.37754

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.

• 出版日期2018-7-13