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10.1038/s41419-017-0130-4

http://scihub22266oqcxt.onion/10.1038/s41419-017-0130-4
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suck abstract from ncbi


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pmid29371591
      Cell+Death+Dis 2018 ; 9 (2 ): 107
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  • MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS #MMPMID29371591
  • Shvil N ; Banerjee V ; Zoltsman G ; Shani T ; Kahn J ; Abu-Hamad S ; Papo N ; Engel S ; Bernhagen J ; Israelson A
  • Cell Death Dis 2018[Jan]; 9 (2 ): 107 PMID29371591 show ga
  • Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the progressive loss of motor neurons in the brain and spinal cord. It has been suggested that toxicity of mutant SOD1 results from its misfolding, however, it is yet unclear why misfolded SOD1 accumulates specifically within motor neurons. We recently demonstrated that macrophage migration inhibitory factor (MIF)-a multifunctional protein with cytokine/chemokine activity and cytosolic chaperone-like properties-inhibits the accumulation of misfolded SOD1. Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells. In addition, MIF alters the typical SOD1 amyloid aggregation pathway in vitro, and, instead, promotes the formation of disordered aggregates, as measured by Thioflavin T (ThT) assay and transmission electron microscopy (TEM) imaging. Moreover, we report that MIF reduces the toxicity of misfolded SOD1 by directly interacting with it, and that the chaperone function and protective effect of MIF in neuronal cultures do not require its intrinsic catalytic activities. Importantly, we report that the locked-trimeric MIF(N110C) mutant, which exhibits strongly impaired CD74-mediated cytokine functions, has strong chaperone activity, dissociating, for the first time, these two cellular functions. Altogether, our study implicates MIF as a potential therapeutic candidate in the treatment of ALS.
  • |*Protein Folding/drug effects [MESH]
  • |Active Transport, Cell Nucleus/drug effects [MESH]
  • |Amyloid/*chemistry [MESH]
  • |Amyotrophic Lateral Sclerosis/metabolism/*pathology [MESH]
  • |Biocatalysis [MESH]
  • |Cell Line [MESH]
  • |Cell Nucleus/drug effects/metabolism [MESH]
  • |Humans [MESH]
  • |Macrophage Migration-Inhibitory Factors/*pharmacology [MESH]
  • |Models, Biological [MESH]
  • |Mutant Proteins/metabolism/toxicity [MESH]
  • |Protein Aggregates/*drug effects [MESH]
  • |Protein Binding/drug effects [MESH]
  • |Protein Multimerization/drug effects [MESH]
  • |Recombinant Proteins/pharmacology [MESH]


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