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Published on: August 10, 2018
Targeting low levels of MIF expression as a potential therapeutic strategy for ALS
Leenor Alfahel1, Thomas Gschwendtberger2, Velina Kozareva3
1Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel; The School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel.
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.
Insights
Peripheral administration of macrophage migration inhibitory factor (MIF) improves motor function and survival in mouse models of amyotrophic lateral sclerosis (ALS). This neuroprotective factor also reduces inflammation and misfolded SOD1 protein, offering a potential ALS therapy.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to SOD1 mutations and motor neuron (MN) loss.
- Macrophage migration inhibitory factor (MIF) is found at low levels in spinal MNs but inhibits mutant SOD1 misfolding and toxicity.
Purpose of the Study:
- To investigate the therapeutic potential of peripheral macrophage migration inhibitory factor (MIF) administration in a mouse model of SOD1-linked ALS.
- To assess the impact of MIF on motor function, disease progression, neuroinflammation, and molecular pathways in ALS.
Main Methods:
- Adeno-associated virus (AAV)-mediated delivery of MIF into adult SOD1G37R mice.
- Assessment of motor function, survival, neuroinflammation, and misfolded SOD1.
- Proteomic and transcriptomic analyses to identify dysregulated pathways.
- Analysis of MIF levels in human ALS patient-derived cells and tissues.
Main Results:
- Peripheral MIF administration significantly improved motor function, delayed disease progression, and extended survival in SOD1G37R mice.
- MIF treatment reduced neuroinflammation, decreased misfolded SOD1 accumulation, and rescued motor neurons.
- Proteomics and transcriptomics revealed correction of dysregulated pathways following MIF treatment.
- Low MIF levels were observed in human familial and sporadic ALS patient-derived cells and tissues.
Conclusions:
- Peripheral MIF delivery is a promising therapeutic strategy for ALS, effectively modulating misfolded SOD1 in vivo.
- MIF administration demonstrates neuroprotective effects and improves disease outcomes in a preclinical ALS model.
- The findings suggest that restoring MIF levels could be a viable therapeutic approach for ALS patients.
