MIF protein slows disease progression in ALS mice, study finds

Boosting MIF levels helped muscle strength, motor function

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Increasing levels of the MIF protein may be a promising therapeutic strategy for slowing disease progression in amyotrophic lateral sclerosis (ALS), a study found.

This approach in a mouse model of ALS with mutations in the SOD1 gene preserved motor function and prolonged survival, while lowering neuroinflammation and restoring gene activity and protein production.

The findings, from a team led by scientists at Ben-Gurion University of the Negev in Israel, “underscore MIF’s potential as a therapeutic candidate for ALS, opening up new possibilities for treatment,” according to a university press release.

The study, “Targeting low levels of MIF expression as a potential therapeutic strategy for ALS,” was published in Cell Reports Medicine.

Nerve cells derived from people with ALS from a variety of underlying causes consistently showed diminished MIF levels, indicating that the approach could be clinically relevant for most ALS patients.

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Gene mutations and misfolded proteins

In ALS, the nerve cells involved in voluntary muscle control — called motor neurons — progressively degenerate. About 90% of ALS cases are sporadic, meaning they arise without a clear pattern or family history. But for the remaining 10%, there is a family history of disease.

Mutations in the SOD1 gene cause up to 20% of these familial ALS cases, and are also found in up to 2% of sporadic cases. It’s been shown that these mutations cause production of a misfolded SOD1 protein that toxically accumulates in motor neurons, but the reason these cells are specifically targeted isn’t known.

MIF, short for macrophage migration inhibitory factor, is a pro-inflammatory molecule that’s released from immune cells. Members of the research team previously identified that the protein also works to inhibit the accumulation of misfolded SOD1, but its levels are naturally low in motor neurons, possibly explaining their vulnerability to SOD1 accumulation.

In a mouse model of ALS carrying mutations in the SOD1 gene, boosting levels of MIF before symptoms emerged significantly delayed disease onset and extended survival.

In the new study, the team aimed to evaluate whether increasing MIF levels when SOD1-ALS mice were already symptomatic could have similar benefits. According to the researchers, this is a “more therapeutically relevant approach,” since treatment doesn’t start until after disease onset.

To increase MIF levels, the gene encoding the protein was packaged in a viral carrier and injected into the bloodstream. The virus helped the gene be taken up by cells of the nervous system, where it would then be used to make more MIF protein (MIF overexpression).

The researchers tested two versions of the MIF protein: a normal version and one with a mutation which had been found in lab studies to lead to better SOD1 inhibition. The two had similar therapeutic effects.

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Disease progression slowed with MIF

The therapies effectively reached motor neurons in the brain and spinal cord, and treated mice exhibited preserved muscle strength and motor function, slower disease progression, and extended survival relative to mice in whom MIF was not overexpressed.

Additional experiments with the normal version of MIF showed that MIF overexpression also reduced misfolded SOD1 accumulation and preserved motor neurons in the spinal cord. Beyond SOD1, the protein appeared to influence a diverse range of disease-associated pathways.

Specifically, it was associated with reductions in neuroinflammation and partial normalizations in gene activity and protein levels that were dysregulated in the ALS model. These genes and proteins were related to a range of biological processes, including inflammation, nerve cell development, and metabolism.

To further explore the role of MIF in ALS patients, the scientists looked at MIF levels in motor neurons derived from induced stem cells of familial ALS patients with mutations in the C9orf72 gene, the TARDBP gene, and the FUS gene.

The data showed that MIF levels were diminished, regardless of the underlying genetic cause. Moreover, the protein was reduced in brain and spinal cord tissue from people with sporadic ALS, indicating that MIF might play a role in ALS beyond SOD1 cases.

MIF overexpression in the motor neurons derived from SOD1-ALS patients led to significant reductions in misfolded SOD1, “further confirming the relevance of this therapeutic concept,” the researchers wrote.

More studies are needed to fully uncover the mechanisms by which MIF is effective in ALS and how the findings might be translated into therapeutic approaches for ALS patients, the researchers said.