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Research Article

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

Marcel F. Leyton-Jaimes, Clara Benaim, Salah Abu-Hamad, Joy Kahn, Amos Guetta, Richard Bucala, and Adrian Israelson
PNAS September 6, 2016 113 (36) 10198-10203; first published August 22, 2016; https://doi.org/10.1073/pnas.1604600113
Marcel F. Leyton-Jaimes
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
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Clara Benaim
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
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Salah Abu-Hamad
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
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Joy Kahn
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
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Amos Guetta
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
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Richard Bucala
bDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT 06520;
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Adrian Israelson
aDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel;
cThe Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
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  • For correspondence: adriani@bgu.ac.il
  1. Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved July 13, 2016 (received for review March 30, 2016)

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Significance

Amyotrophic lateral sclerosis (ALS) can be caused by mutations in superoxide dismutase (SOD1), which lead to the accumulation of misfolded SOD1 proteins and to the death of motor neurons. Here we show that endogenous macrophage migration inhibitory factor (MIF) acts as a chaperone for misfolded SOD1 in vivo, because completely eliminating MIF in a mutant SOD1 mouse model of familial ALS enhanced the accumulation of misfolded SOD1, accelerated disease onset and late disease progression, and shortened the lifespan of mice expressing mutant SOD1. This study thus sheds light on the important implications of modulating MIF levels and provides insight into the potential therapeutic role of MIF in suppressing the selective accumulation of misfolded SOD1 in 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 SOD1G85R 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 SOD1G85R-MIF−/− mice than in their SOD1G85R-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 SOD1G85R 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.

  • ALS
  • mutant SOD1 mouse
  • mutant SOD1
  • misfolded SOD1
  • MIF

Footnotes

  • ↵1M.F.L.-J., C.B., and S.A.-H. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: adriani{at}bgu.ac.il.
  • Author contributions: M.F.L.-J., C.B., S.A.-H., J.K., and A.I. designed research; M.F.L.-J., C.B., S.A.-H., J.K., and A.G. performed research; R.B. contributed new reagents/analytic tools; M.F.L.-J., C.B., S.A.-H., J.K., and A.I. analyzed data; and A.I. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604600113/-/DCSupplemental.

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MIF reduces misfolded SOD1 toxicity in ALS
Marcel F. Leyton-Jaimes, Clara Benaim, Salah Abu-Hamad, Joy Kahn, Amos Guetta, Richard Bucala, Adrian Israelson
Proceedings of the National Academy of Sciences Sep 2016, 113 (36) 10198-10203; DOI: 10.1073/pnas.1604600113

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MIF reduces misfolded SOD1 toxicity in ALS
Marcel F. Leyton-Jaimes, Clara Benaim, Salah Abu-Hamad, Joy Kahn, Amos Guetta, Richard Bucala, Adrian Israelson
Proceedings of the National Academy of Sciences Sep 2016, 113 (36) 10198-10203; DOI: 10.1073/pnas.1604600113
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