title: Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS.
abstract: Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type-selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation.
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Shuying
authors.initials: S
authors.lastname: Sun
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Department of Neuroscience, The Ohio State University, Columbus, OH 43205;
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Kevin
authors.initials: K
authors.lastname: Drenner
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Seiya
authors.initials: S
authors.lastname: Tokunaga
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Alex
authors.initials: A
authors.lastname: Kopelevich
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Department of Neuroscience, The Ohio State University, Columbus, OH 43205;
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093 dcleveland@ucsd.edu.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; RNA profiling; SOD1; bacTRAP; cell type selective toxicity