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

Leenor Alfahel, Thomas Gschwendtberger, Velina Kozareva, Laura Dumas, Rachel Gibbs, Alexander Kertser, Kuti Baruch, Shir Zaccai, Joy Kahn, Nadine Thau-Habermann, Reto Eggenschwiler, Jared Sterneckert, Andreas Hermann, Niveda Sundararaman, Vineet Vaibhav, Jennifer E. Van Eyk, Victor F. Rafuse, Ernest Fraenkel, Tobias Cantz, Susanne PetriAdrian Israelson

Research output: Contribution to journalArticlepeer-review


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.

Original languageAmerican English
Article number101546
JournalCell Reports Medicine
Issue number5
StatePublished - 21 May 2024


  • AAV
  • ALS
  • MIF
  • familial ALS
  • iPSCs
  • misfolded SOD1
  • motor neurons
  • mutant SOD1
  • mutant SOD1 mouse
  • sporadic ALS

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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