The majority of ALS-associated mutations in the superoxide dismutase 1 (SOD1) protein cause it to misfold and form toxic aggregates. In motor neurons (MNs) specifically, the misfolded protein accumulates on the surface of mitochondria and the ER and inhibits their normal function (see July 2011 news). Why the specificity for MNs? Researchers have proposed that the chaperone macrophage migration inhibitory factor (MIF) may play a role, since it promotes proper folding of mutant SOD1 (mSOD1) but is not expressed in motor neurons (see March 2015 news). A report in the September 6 PNAS, led by Adrian Israelson from Ben Gurion University of the Negev, Israel, provides further support for the importance of MIF. Mutant SOD1 mice lacking MIF expression accumulated higher levels of misfolded SOD1 and had a shorter lifespan as compared to MIF-expressing mSOD1 mice. Augmenting MIF expression in neuronal cultures reduced mSOD1-induced cell death. These findings suggest that MIF could provide a potential therapeutic target for SOD1-ALS.
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Leyton-Jaimes MF, Benaim C, Abu-Hamad S, Kahn J, Guetta A, Bucala R, Israelson A. Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10198-203. [Pubmed].