Targeting low levels of MIF expression as a potential therapeutic strategy for ALS

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neuron (MN) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1G37R mice significantly improves their motor function, delays disease progression, and extends survival. Moreover, MIF treatment reduces neuroinflammation and misfolded SOD1 accumulation, rescues MNs, and corrects dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we reveal low MIF levels in human induced pluripotent stem cell-derived MNs from familial ALS patients with different genetic mutations, as well as in post mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients. [Display omitted] •Systemic AAV/PhPeB MIF administration after ALS onset extends SOD1G37R mice survival•MIF positively affects pathways, including inflammation, neurogenesis, and metabolism•Low MIF in iPSCs-MNs of SOD1, C9orf72, and TDP43 patients correspond with murine data•Low levels of MIF are present in the motor cortex and spinal cord of sALS patients Alfahel et al. demonstrate that systemically administered MIF following disease onset extends survival of SOD1G37R mice, functioning as both a misfolded SOD1 chaperone and also affecting diverse cellular pathways. Importantly, low MIF levels are present in fALS and sALS patients, corresponding to low levels previously revealed in SOD1 mice.