MIF homolog d-dopachrome tautomerase (D-DT/MIF-2) does not inhibit accumulation and toxicity of misfolded SOD1

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons. About 20% of familial ALS cases are caused by dominant mutations in SOD1. It has been suggested that toxicity of mutant SOD1 results from its misfolding, however, it is unclear why misfolded SOD1 accumulates within specific tissues. We have demonstrated that macrophage migration inhibitory factor (MIF), a multifunctional protein with cytokine/chemokine and chaperone-like activity, inhibits the accumulation and aggregation of misfolded SOD1. Although MIF homolog, D-dopachrome tautomerase (D-DT/MIF-2), shares structural and genetic similarities with MIF, its biological function is not well understood. In the current study, we investigated, for the first time, the mechanism of action of D-DT in a model of ALS. We show that D-DT inhibits mutant SOD1 amyloid aggregation in vitro, promoting the formation of amorphous aggregates. Moreover, we report that D-DT interacts with mutant SOD1, but does not inhibit misfolded mutant SOD1 accumulation and toxicity in neuronal cells. Finally, we show that D-DT is expressed mainly in liver and kidney, with extremely low expression in brain and spinal cord of adult mice. Our findings contribute to better understanding of D-DT versus MIF function in the context of ALS.

The Role of Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (D-DT/MIF-2) in Infections: A Clinical Perspective

“…In contrast, MIF and DDT play a different role in physiological processes such as adipogenesis and correlate differently with obesity [122]. D-DT has so far shown interesting results when applied in studies on spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, tumors, skin diseases, heart failure, myocardial infarction, alveolar repair, orthotopic liver transplantation, and sepsis [61,121,[125][126][127][128][129][130][131][132][133][134].…”

Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer

“…Various studies have revealed that D-dopachrome tautomerase (D-DT, also known as MIF-2) is a functional homolog of MIF, since both have a similar gene structure, 3D architecture, and enzyme activity 11 , 24 – 26 . D-DT shares several biological activities with MIF and could therefore represent an endogenous amplifier of MIF action 21 , 27 , 28 ; however, divergent effects have also been reported 28 , 29 .…”