Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved July 13, 2016 (received for review March 30, 2016)
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.
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.
↵1M.F.L.-J., C.B., and S.A.-H. contributed equally to this work.
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.
