A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress.

Autor:	Thams S; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Electronic address: sebastian.thams@ki.se., Lowry ER; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Larraufie MH; Department of Biological Sciences and Department of Chemistry, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA., Spiller KJ; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Li H; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Williams DJ; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, 650 West 168th Street, New York, NY, USA., Hoang P; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Jiang E; Department of Biological Sciences and Department of Chemistry, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA., Williams LA; Department of Stem Cell and Regenerative Biology, Harvard University, MA 02138, USA., Sandoe J; Department of Stem Cell and Regenerative Biology, Harvard University, MA 02138, USA., Eggan K; Department of Stem Cell and Regenerative Biology, Harvard University, MA 02138, USA., Lieberam I; Centre for Stem Cells and Regenerative Medicine and MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 9RT, UK., Kanning KC; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Stockwell BR; Department of Biological Sciences and Department of Chemistry, Columbia University, Northwest Corner Building, MC4846, 550 West 120th Street, New York, NY 10027, USA., Henderson CE; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA., Wichterle H; Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA; Departments of Neuroscience, Rehabilitation and Regenerative Medicine, and Neurology, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USA. Electronic address: hw350@cumc.columbia.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2019 Jan 02; Vol. 27 (1), pp. 87-101. Date of Electronic Publication: 2018 Oct 19.
DOI:	10.1016/j.ymthe.2018.10.010
Abstrakt:	Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential motor neuron susceptibility remain elusive. We developed a stem cell-based motor neuron assay to study cell-autonomous mechanisms causing motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived motor neurons were more sensitive than interneurons. CPA induced endoplasmic reticulum stress and the unfolded protein response. Furthermore, CPA resulted in an accelerated degeneration of motor neurons expressing human superoxide dismutase 1 (hSOD1) carrying the ALS-causing G93A mutation, compared to motor neurons expressing wild-type hSOD1. A secondary screen identified compounds that alleviated CPA-mediated motor neuron degeneration: three kinase inhibitors and tauroursodeoxycholic acid (TUDCA), a bile acid derivative. The neuroprotective effects of these compounds were validated in human stem cell-derived motor neurons carrying a mutated SOD1 allele (hSOD1 A4V ). Moreover, we found that the administration of TUDCA in an hSOD1 G93A mouse model of ALS reduced muscle denervation. Jointly, these results provide insights into the mechanisms contributing to the preferential susceptibility of ALS motor neurons, and they demonstrate the utility of stem cell-derived motor neurons for the discovery of new neuroprotective compounds. (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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