@article{790c1bddac2241118258c5389cd5a37d,
title = "Abnormal RNA stability 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 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.",
author = "Tank, {E. M.} and C. Figueroa-Romero and Hinder, {L. M.} and K. Bedi and Archbold, {H. C.} and X. Li and K. Weskamp and N. Safren and X. Paez-Colasante and C. Pacut and S. Thumma and Paulsen, {M. T.} and K. Guo and J. Hur and M. Ljungman and Feldman, {E. L.} and Barmada, {S. J.}",
note = "Funding Information: We thank the study participants and their families; Dr. Stephen A. Goutman, Director of the University of Michigan ALS Clinic and Biorepository; Dr. Benjamin Reubinoff for assistance with fibroblast reprogramming; Drs. Henry Paulson and Vivian G. Cheung for advice and discussions; Dr. Benjamin J. Murdock, Ms. Maegan A. Tabby, and Ms. Carey Backus for technical support with the flow cytometry, immunofluorescence, and tissue culture; Ms. Hayley J. Petit, Ms. Katharina Kretzler, Ms. Olivia Kirby, and Ms. Elise Tuneff for technical support analyzing mitochondria morphology; Drs. Stephen Lentz and Amy Rumora for their assistance using the A1 Nikon confocal microscope for the mitochondria morphology analysis; Dr. Sasha Meshinchi for his help with imaging; Drs. David B. Lombard and Surinder Kumar for technical support with bioenergetics analysis; Dr. Venkatesha Basrur for assistance with proteomics; the Proteomics Resource Facility at the University of Michigan; the DNA Sequencing Core at the University of Michigan; and Mr. Matthew D. Perkins who assisted with postmortem tissue from the Michigan Brain Bank and the Michigan ALS Consortium. The present work was supported in part by funding from the National Institutes of Health (NIH) National Institute for Neurological Disorders and Stroke (NINDS) R01 NS097542, and National Institute for Aging (NIA) P30 AG053760, the Association for Frontotemporal Degeneration, Active Against ALS, the Robert Packard Center for ALS Research, the M-Cubed Program at the University of Michigan, the Protein Folding Diseases Initiative at the University of Michigan, the Program for Neurology Research and Discovery, the University of Michigan and the A. Alfred Taubman Medical Research Institute; confocal microscopy was performed at the Microscopy & Image Analysis Core of the Michigan Diabetes Research Center funded by National Institutes of Health grant P60DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases; skin samples from the study participants were obtained in collaboration with the Michigan Institute for clinical and Health Research at the University of (MICHR, UL1TR000433). Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-05049-z",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}