Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA479536 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7469670_1.fastq.gz | Fastqsanger.gz | |||
| SRR7469670_2.fastq.gz | Fastqsanger.gz | |||
| SRR7469680_1.fastq.gz | Fastqsanger.gz | |||
| SRR7469680_2.fastq.gz | Fastqsanger.gz | |||
| SRR7469690_1.fastq.gz | Fastqsanger.gz |
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Project description: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. Here we show unexpectedly that the signature of hnRNP H sequestration and altered splicing of target transcripts we identified in C9ALS patients (Conlon et al. 2016) also occurs in fully half of 50 post-mortem sporadic, non-C9 ALS/FTD post-mortem 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.
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Project description: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.
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Project description:To differentiate, characterize and examine intrinsic phenotypes of C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG). Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features.
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