Abnormal RNA stability in amyotrophic lateral sclerosis

E. M. Tank, C. Figueroa-Romero, L. M. Hinder, K. Bedi, H. C. Archbold, X. Li, K. Weskamp, N. Safren, X. Paez-Colasante, C. Pacut, S. Thumma, M. T. Paulsen, K. Guo, J. Hur, M. Ljungman, E. L. Feldman, S. J. Barmada

Research output: Contribution to journalArticle

23 Scopus citations

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 postmortem 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.

Original languageEnglish (US)
Article number2845
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Tank, E. M., Figueroa-Romero, C., Hinder, L. M., Bedi, K., Archbold, H. C., Li, X., Weskamp, K., Safren, N., Paez-Colasante, X., Pacut, C., Thumma, S., Paulsen, M. T., Guo, K., Hur, J., Ljungman, M., Feldman, E. L., & Barmada, S. J. (2018). Abnormal RNA stability in amyotrophic lateral sclerosis. Nature communications, 9(1), [2845]. https://doi.org/10.1038/s41467-018-05049-z