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, Adrian Israelson

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 SO?G85R -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 upregulating MIF within the nervous system to modulate the selective accumulation of misfolded SOD1.

Original languageEnglish
Pages (from-to)10198-10203
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number36
DOIs
StatePublished - 6 Sep 2016

Keywords

  • ALS|mutant sod1 mouse
  • Mutant sod1|misfolded sod1|mif

ASJC Scopus subject areas

  • General

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