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2018 ; 9
(2
): 107
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MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates:
implications for familial ALS
#MMPMID29371591
Shvil N
; Banerjee V
; Zoltsman G
; Shani T
; Kahn J
; Abu-Hamad S
; Papo N
; Engel S
; Bernhagen J
; Israelson A
Cell Death Dis
2018[Jan]; 9
(2
): 107
PMID29371591
show ga
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis
(ALS), a fatal neurodegenerative disease caused by the progressive loss of motor
neurons in the brain and spinal cord. It has been suggested that toxicity of
mutant SOD1 results from its misfolding, however, it is yet unclear why misfolded
SOD1 accumulates specifically within motor neurons. We recently demonstrated that
macrophage migration inhibitory factor (MIF)-a multifunctional protein with
cytokine/chemokine activity and cytosolic chaperone-like properties-inhibits the
accumulation of misfolded SOD1. Here, we show that MIF inhibits mutant SOD1
nuclear clearance when overexpressed in motor neuron-like NSC-34 cells. In
addition, MIF alters the typical SOD1 amyloid aggregation pathway in vitro, and,
instead, promotes the formation of disordered aggregates, as measured by
Thioflavin T (ThT) assay and transmission electron microscopy (TEM) imaging.
Moreover, we report that MIF reduces the toxicity of misfolded SOD1 by directly
interacting with it, and that the chaperone function and protective effect of MIF
in neuronal cultures do not require its intrinsic catalytic activities.
Importantly, we report that the locked-trimeric MIF(N110C) mutant, which exhibits
strongly impaired CD74-mediated cytokine functions, has strong chaperone
activity, dissociating, for the first time, these two cellular functions.
Altogether, our study implicates MIF as a potential therapeutic candidate in the
treatment of ALS.