An increase in macrophage migration inhibitory factor (MIF) may treat ALS, study finds

A team headed by Israeli researchers with colleagues in North America and Germany have suggested that increase macrophage migration inhibitory factor (MIF) protein levels could treat amyotrophic lateral sclerosis (ALS) – commonly known as Lou Gehrig’s disease (named for the Yankee baseball star who succumbed to it) – the devastating neurodegenerative condition of progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure, and death.

The collaborative research study just published in the prestigious Cell Press journal Cell Reports Medicine under the title “Tageting low levels of MIT expression as a potential therapeutic strategy for ALS” presents a promising therapeutic technique for treating ALS. 

ALS, the most common motor neuron disease in adults, is a fatal neurodegenerative disorder characterized by selective degeneration of both upper and lower motor neurons. About 90% of cases are sporadic with no genetic connection. While its cause remains elusive in most cases, a subset of about 10% is attributed to genetic factors. 

Typically striking men and women aged 40 to 60, ALS carries a grim prognosis with a median survival of two to five years after diagnosis. About a fifth of genetic ALS cases result from mutations in the superoxide dismutase (SOD1) gene. Extensive research has found that these mutations – numbering over 180 variants – induce motor neuron degeneration via some form of toxicity. However, the precise mechanisms driving this selective toxicity remain unresolved. 

Multifunctional protein MIF inhibits mutant SOD1

A few years ago, Ben-Gurion University (BGU) of the Negev Prof. Adrian Israelson and colleagues identified the multifunctional protein MIF to directly inhibit mutant SOD1, misfolding and binding to intracellular organelles (subcellular structures that have specific jobs to carry out in the cell). Elevated expression of MIF was shown to suppress accumulation of misfolded SOD1 and extends survival of mutant SOD1-expressing motor neurons. 

The new study led by Dr. Leenor Alfahel at Israelson’s BGU lab at, in collaboration with Prof. Susanne Petri’s team at Hannover Medical School in Germany and other international collaborators, proved the efficacy of exogenous MIF administration via viral vectors in a SOD1 mouse model of ALS. 

This intervention effectively delays motor function decline, modulates critical pathways, and extends lifespan. Moreover, the study identifies diminished MIF levels in motor neurons derived from familial ALS patients with various genetic backgrounds, as well as in the motor cortex and spinal cord of sporadic ALS cases, suggesting broader implications beyond SOD1-linked pathology. 

The team members said that their collaborative efforts underscored MIF's potential as a therapeutic candidate for ALS, opening up new possibilities for treatment. However, comprehensive investigations are warranted to fully elucidate the underlying mechanisms of MIF's efficacy and its translational implications.