. Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron. 2015 Apr 8;86(1):218-32. Epub 2015 Mar 19 PubMed.


Please login to recommend the paper.


  1. This is really a remarkable paper, speaking directly to the problem of motor neuron vulnerability in SOD1 familial ALS and mutant SOD1 mouse models. The authors have systematically sought and identified a chaperone activity in non-neuronal cells that protects from the mitochondrial and ER dysfunction observed with mutant SOD1. That chaperone activity was found to be due to macrophage inhibitory factor. This discovery leads to new and previously unanticipated treatment avenues for SOD1 FALS, and perhaps also sporadic ALS, in which wild-type SOD1 has been observed to be misfolded.

  2. The study by Israelson et al. identifies a chaperone, MIF, which facilitates SOD1 folding. They report that MIF is of low abundance in motor neurons and might lie at the heart of why SOD1 becomes misfolded and associated with mitochondria. The work is a step forward in our understanding of how mitochondria become coated with and damaged by misfolded SOD1. The findings stimulate many questions. What is the relationship between MIF and the well-characterized copper chaperone of SOD1, CCS? What are the other client proteins of MIF? Is MIF broadly relevant to ALS? Is TDP-43 or FUS protein-folding mediated by MIF, or is it really specific for SOD1? Moreover, what is the broader expression pattern of MIF? There is clearly a deficiency of MIF in motor neurons, but what about other neuronal types? Is MIF relevant to other neurodegenerative diseases where protein misfolding is prevalent?

    MIF may represent an interesting therapeutic target. The studies presented here are an excellent start toward that goal. It would be ideal to demonstrate that introduction of neuronal MIF is sufficient to rescue disease in the animal model. Given that misfolded SOD1 seems to accumulate more in motor neurons, the lack of MIF may speak directly to disease initiation. However, given that MIF is a cytokine and critical regulator of the innate immune response, I expect that there are challenges ahead.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. Motor Neuron Vulnerability: The Case of the Missing Chaperone?