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  • Title: Targeting low levels of MIF expression as a potential therapeutic strategy for ALS.
    Author: Alfahel L, Gschwendtberger T, Kozareva V, Dumas L, Gibbs R, Kertser A, Baruch K, Zaccai S, Kahn J, Thau-Habermann N, Eggenschwiler R, Sterneckert J, Hermann A, Sundararaman N, Vaibhav V, Van Eyk JE, Rafuse VF, Fraenkel E, Cantz T, Petri S, Israelson A.
    Journal: Cell Rep Med; 2024 May 21; 5(5):101546. PubMed ID: 38703766.
    Abstract:
    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.
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