Macrophage Migration Inhibitory Factor as a Chaperone Inhibiting Accumulation of Misfolded SOD1

Abstract

Summary Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in non-neuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity.

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

“…For example, MIF accumulation was very low within spinal neuronal cells (Fig. S3), confirming our previous observations using rat spinal cord tissues (22).…”

“…Quantitative analysis of misfolded SOD1 was performed from duplicates or triplicates from different mice (between two and four mice for each genotype at each disease stage) using ImageJ software and Student's t test. **P < 0.01. that the association of mutant SOD1 with the mitochondria and ER can be suppressed by cytosolic MIF, which inhibits the accumulation of misfolded SOD1 (22). In addition, we have shown that MIF levels are low within the cell bodies of motor neurons, and that increasing MIF levels extends the survival of motor neurons in culture.…”

“…MIF is a 12-kDa protein that has been implicated in both extracellular and intracellular functions and is synthesized as a cytoplasmic protein (22). The cytokine activity of MIF is achieved by posttranslational sequestration of the cytoplasmic MIF into vesicles, followed by its release, through an as-yet unidentified mechanism, in response to a variety of signals (29).…”

“…After establishing that (i) MIF acts as a chaperone for misfolded SOD1 (22) and protects from mutant SOD1-induced cell death (Fig. 1), (ii) endogenous MIF inhibits the association of misfolded SOD1 with intracellular membranes (Fig.…”

“…The molecular determinants that underlie the selective accumulation and binding of misfolded mutant SOD1 to the spinal cord mitochondria and ER remain unknown; however, we recently found that macrophage migration inhibitory factor (MIF) acts as a cytosolic chaperone that inhibits mutant SOD1 misfolding onto the mitochondria and ER, with extremely low MIF levels within the cytosol of motor neurons (22).…”