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An innovative approach to ALS disease: increasing MIF protein levels in nerve cells

An international study by Ben-Gurion University of the Negev in collaboration with colleagues from Germany, the USA and Canada, delved into the potential of increasing protein levels (MIF) as a new approach to dealing with muscular dystrophy (ALS). The findings of the innovative study were published in the prestigious journal Cell Report Medicine.

Link to the image of the spinal cords (photo: Dr. Linor Alfahal, from the journal Cell (Reports Medicine. On the left - a section of the spinal cord of a mouse expressing the disease without treatment, and on the right a section of the spinal cord of a mouse expressing the disease and treated with MIF:
Link to the picture of the spinal cords (Photograph: Dr. Linor Alfahal, from the journal Cell (Reports Medicine. On the left - a section of the spinal cord of a mouse expressing the disease without treatment, and on the right a section of the spinal cord of a mouse expressing the disease and treated with MIF

ALS disease, often called Lou Gehrig's disease, is a condition in which certain areas of the brain do not function at all and is known among the most difficult diseases to cure. This neurological condition is characterized by progressive loss of motor neurons, leading to muscle weakness, paralysis and eventually respiratory failure.

The causes of the disease are not completely known, but a subgroup of about 10% of patients with the disease are attributed to genetic factors. Most often, the disease begins between the ages of 40 and 60, and its medical prognosis is difficult, with a survival of two to five years after diagnosis.

About 20% of genetic ALS cases result from mutations in a gene called superoxide dismutase (SOD1). Extensive research has shown that these mutations, of which there are more than 180 different variants, cause degeneration of the motor neurons by creating toxicity. However, the mechanisms driving this toxicity remain unresolved.

some years ago, Prof. Adrian Israelson from the Department of Physiology and Cell Biology at Ben-Gurion University of the Negev, together with his colleagues from the University of California, San Diego, discovered that the protein Macrophage migration inhibitory factor (MIF) prevents the accumulation of the defective SOD1 protein in the cell. An increase in the expression level of MIF, increases the vitality of different nerve cells, including motor nerve cells which express different mutations associated with ALS.

Recently, research led Dr. Linor Alfahal in the laboratory of Professor Adrian Israelson at Ben Gurion University of the Negev, in collaboration with the team of Professor Susan Petrie from the Medical School in Hannover, Germany, together with other international partners, demonstrated the effectiveness of MIF protein expression in cell culture and in a mouse model simulating the ALS disease. The mice genetically express a defective human SOD1 gene and therefore they express symptoms similar to the symptoms of the ALS patients. The MIF protein is given to mice by injecting a virus that expresses the protein.

This intervention in mice was able to delay the decline in motor function that manifests itself in tremors and deteriorates into paralysis, regulate critical biological pathways affected by the disease and extend their lifespan. Furthermore, the study identified reduced MIF protein levels in motor neurons derived from ALS patients with a genetic background, even from different genetic backgrounds.

"In the model we used, we noticed motor symptoms that were manifested in tremors in the legs that developed over time into paralysis. The treatment succeeded in slowing down this motor deterioration," explained Prof. Israelson. "In testing the expression of the proteins in the spinal cord fluid of the mice and the gene expression in the spinal cord, we found that some of the biological pathways that were damaged as a result of the disease were repaired."

The study also found that the reduced MIF protein levels were also found in the motor cortex and spinal cord of sporadic ALS patients, indicating broader implications beyond SOD1-related pathology.

” The data obtained highlight the potential of MIF as a therapeutic candidate for ALS. Of course, it is necessary to continue to investigate and fully understand the mechanisms of efficiency and the consequences of its applied translation", Prof. Israelson concluded.

The research group included: Linor Elfahal, Shir Zakai, Joy Kahn and Adrian Israelson from Ben Gurion University of the Negev, Thomas Geschwandtberger, Nadine Thao-Haverman, Reto Eggenschwiler, Tobias Kanz and Susan Petri from the University of Hanover, Germany, and Lina Kozerva and Ernst Frankel from the MIT Institute in the USA. B, Laura Deumas, Rachel Gibbs, Victor Rapos from Dalhousie University in Canada, Alexander Kratzer and Coty Baruch from the ImmunoBrain Checkpoint Company, Jared Sternkert from the University of Dresden in Germany, Andreas Herrmann from the University of Rostock in Germany, Nivada Sundaraman, Vinet Vaibhav and Jennifer Van Eyck from the Medical Center Cedars Seiney in Los Angeles, USA.

This research (grant number 284/19) was supported by the National Science Foundation (ISF). Also, this research was supported by a grant (No. 116-415.6-2016) from the GIF Foundation, the German-Israeli Foundation for Scientific Research and Development.

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