title: Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS.
abstract: Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons in the brain and spinal cord. It has been suggested that the toxicity of mutant SOD1 results from its misfolding and accumulation on the cytoplasmic faces of intracellular organelles, including the mitochondria and endoplasmic reticulum (ER) of ALS-affected tissues. Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit the accumulation of misfolded SOD1 and its binding to intracellular membranes, but the role of endogenous MIF in modulating SOD1 misfolding in vivo remains unknown. To elucidate this role, we bred MIF-deficient mice with SOD1(G85R) mice, which express a dismutase-inactive mutant of SOD1 and are considered a model of familial ALS. We found that the accumulation of misfolded SOD1, its association with mitochondrial and ER membranes, and the levels of sedimentable insoluble SOD1 aggregates were significantly higher in the spinal cords of SOD1(G85R)-MIF(-/-) mice than in their SOD1(G85R)-MIF(+/+) littermates. Moreover, increasing MIF expression in neuronal cultures inhibited the accumulation of misfolded SOD1 and rescued from mutant SOD1-induced cell death. In contrast, the complete elimination of endogenous MIF accelerated disease onset and late disease progression and shortened the lifespan of the SOD1(G85R) mutant mice. These findings indicate that MIF plays a significant role in the folding and misfolding of SOD1 in vivo, and they have implications for the potential therapeutic role of up-regulating MIF within the nervous system to modulate the selective accumulation of misfolded SOD1.
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Leyton-Jaimes
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
authors.forename: Clara
authors.initials: C
authors.lastname: Benaim
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
authors.forename: Salah
authors.initials: S
authors.lastname: Abu-Hamad
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
authors.forename: Joy
authors.initials: J
authors.lastname: Kahn
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
authors.forename: Amos
authors.initials: A
authors.lastname: Guetta
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel adriani@bgu.ac.il.
authors.forename: Adrian
authors.initials: A
authors.lastname: Israelson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D066329:Protein Aggregates; D017510:Protein Folding; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D066329:Protein Aggregates; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: ALS; MIF; misfolded SOD1; mutant SOD1; mutant SOD1 mouse