title: Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1.
abstract: Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity.
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences and The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel. Electronic address: adriani@bgu.ac.il.
authors: Adrian
authors: A
authors: Israelson
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Dara
authors: D
authors: Ditsworth
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Shuying
authors: S
authors: Sun
authors: The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH 43205, USA; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43205, USA.
authors: SungWon
authors: S
authors: Song
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Jason
authors: J
authors: Liang
authors: Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Marian
authors: M
authors: Hruska-Plochan
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Melissa
authors: M
authors: McAlonis-Downes
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences and The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel.
authors: Salah
authors: S
authors: Abu-Hamad
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences and The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel.
authors: Guy
authors: G
authors: Zoltsman
authors: Department of Physiology and Cell Biology, Faculty of Health Sciences and The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel.
authors: Tom
authors: T
authors: Shani
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Marcus
authors: M
authors: Maldonado
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Anh
authors: A
authors: Bui
authors: Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Michael
authors: M
authors: Navarro
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Huilin
authors: H
authors: Zhou
authors: Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Martin
authors: M
authors: Marsala
authors: The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH 43205, USA; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43205, USA; Department of Neuroscience, The Ohio State University, Columbus, OH 43205, USA.
authors: Brian K
authors: BK
authors: Kaspar
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors: Sandrine
authors: S
authors: Da Cruz
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093-0670, USA; Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093-0670, USA. Electronic address: dcleveland@ucsd.edu.
authors: Don W
authors: DW
authors: Cleveland
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D009419:Nerve Tissue Proteins; D012269:Ribosomal Proteins; C098998:Rpl10a protein, rat; C000606290:SOD1 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002795:Choline O-Acetyltransferase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase