RNA instability in amyotrophic lateral sclerosis

ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in post-mortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.

OTHER RELATED OMICS DATASETS IN: GSE115310

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell, Cell Culture

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Sami Barmada  

LAB HEAD: Sami Barmada

PROVIDER: PXD009969 | Pride | 2018-07-24

REPOSITORIES: Pride