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 (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.
|Year of Publication||
2018 07 13
|PubMed Central ID||
R35 GM118136 / GM / NIGMS NIH HHS / United States
MR/M008606/1 / MRC_ / Medical Research Council / United Kingdom
FRATTA/JAN15/946-795 / MNDA_ / Motor Neurone Disease Association / United Kingdom
T32 GM008798 / GM / NIGMS NIH HHS / United States
TURNER/OCT15/972-797 / MNDA_ / Motor Neurone Disease Association / United Kingdom
5T32GM008798 / GM / NIGMS NIH HHS / United States
MALASPINA/APR13/817-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom
R35 GM 118136 / GM / NIGMS NIH HHS / United States
RF1 AG058476 / AG / NIA NIH HHS / United States