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Markmiller S, Sathe S, Server KL, et al. Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress. Cell Rep. 2021;36(10):109685doi: 10.1016/j.celrep.2021.109685.
Markmiller, S., Sathe, S., Server, K. L., Nguyen, T. B., Fulzele, A., Cody, N., Javaherian, A., Broski, S., Finkbeiner, S., Bennett, E. J., Lécuyer, E., Yeo, G. W., & Mark, M. L. S. (2021). Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress. Cell reports, 36(10), 109685. https://doi.org/10.1016/j.celrep.2021.109685
Markmiller, Sebastian, et al. "Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress." Cell reports vol. 36,10 (2021): 109685. doi: https://doi.org/10.1016/j.celrep.2021.109685
Markmiller S, Sathe S, Server KL, Nguyen TB, Fulzele A, Cody N, Javaherian A, Broski S, Finkbeiner S, Bennett EJ, Lécuyer E, Yeo GW, Mark MLS. Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress. Cell Rep. 2021 Sep 07;36(10):109685. doi: 10.1016/j.celrep.2021.109685. PMID: 34496257.
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Cell Rep. 2021 Sep 07;36(10):109685. doi: 10.1016/j.celrep.2021.109685.

Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.

Cell reports

Sebastian Markmiller, Shashank Sathe, Kari L Server, Thai B Nguyen, Amit Fulzele, Neal Cody, Ashkan Javaherian, Sara Broski, Steven Finkbeiner, Eric J Bennett, Eric Lécuyer, Gene W Yeo, Mark

Affiliations

  1. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92039, USA.
  2. Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  3. Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
  4. Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA.
  5. Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Neurology and Physiology, University of California-San Francisco, San Francisco, CA 94158, USA.
  6. Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
  7. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, 92039, USA. Electronic address: [email protected].

PMID: 34496257 DOI: 10.1016/j.celrep.2021.109685

Abstract

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). Here, we assess the impact of stress on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs) using subcellular fractionation with RNA sequencing and proteomics. Transient stress disrupts subcellular RNA and protein distributions, alters the RNA binding profile of SG- and ALS-relevant RBPs and recapitulates disease-associated molecular changes such as aberrant splicing of STMN2. Although neurotypical PSC-MNs re-establish a normal subcellular localization landscape upon recovery from stress, cells harboring ALS-linked mutations are intransigent and display a delayed-onset increase in neuronal cell death. Our results highlight subcellular molecular distributions as predictive features and underscore the utility of cellular stress as a paradigm to study ALS-relevant mechanisms.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: RNA localization; TDP-43; amyotrophic lateral sclerosis (ALS); cellular stress response; hnRNPA2B1; motor neurons; neurodegeneration; nucleocytoplasmic transport; protein aggregation; stress granules

Conflict of interest statement

Declaration of interests G.W.Y. is co-founder, a member of the Board of Directors, a scientific advisor, equity holder, and paid consultant for Locanabio and Eclipse BioInnovations. G.W.Y. is a visiti

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