New therapy option for fatal nerve disease ALS

MHH researchers find innovative approach to prolong the survival of motor nerve cells.

Amyotrophic lateral sclerosis (ALS) is an incurable, severe disease of the nervous system. As the disease progresses, misfolded proteins accumulate in the motor nerve cells responsible for muscle movement in the brain and spinal cord, causing inflammation and permanently damaging these cells, known as motor neurons. The entire musculature becomes increasingly weak and death from respiratory paralysis usually occurs after a few years. There is no cure for ALS; to date, there is only one approved drug that can only delay the progression of the disease. Around 8,000 to 9,000 people are affected in Germany. Around 2,500 people are newly diagnosed with ALS every year, mostly between the ages of 60 and 80. Around 90 percent of cases are sporadic, meaning that the causes of the disease are unknown. In the remainder, it is caused by mutated genes and is inherited. Almost a fifth of them have a gene mutation that leads to a misfolding of the protein SOD1. This protein belongs to the group of superoxide dismutases, which protect the body from oxidative stress and thus from damage to the cells.

Have found a molecular switch to protect the motor nerve cells of ALS patients: Professor Dr. Susanne Petri and Dr. Thomas Gschwendtberger. Copyright: Karin Kaiser/MHH

A research team led by Professor Dr. Susanne Petri, Acting Director of the Department of Neurology with Clinical Neurophysiology at Hannover Medical School (MHH), has discovered that the protein macrophage migration inhibitory factor (MIF) can influence this process. It acts as a signaling molecule against inflammatory processes and prevents SOD1 from accumulating in the motor neurons. In cooperation with scientists from Israel, the researchers have now been able to show that MIF could apparently also slow down the progression of ALS and prolong the survival of nerve fibers in ALS patients with other genetic causes as well as in sporadic cases. The results have been published in the journal “Cell Reports Medicine”.

MIF apparently important for all forms of ALS

“Our cooperation partners in Israel had previously found that the MIF concentration in the brain and spinal cord is significantly reduced in an ALS mouse model with a SOD1 mutation,” says Dr. Thomas Gschwendtberger, scientist at the Department of Neurology and first author of the study, which is part of his doctoral thesis. The protein performs several tasks at once.

On the one hand, it acts as a so-called chaperone and helps SOD1 to fold correctly and thus function properly. Secondly, it prevents misfolded SOD1 proteins from accumulating. MIF also plays an important role in the innate immune response, for example in the acute fight against bacterial infections.

In the current study, the researchers examined nerve tissue from ALS patients. “Here, too, we found significantly less anti-inflammatory MIF than in healthy people in all cases,” emphasizes the chemist. “This means that this protein apparently plays an important role in the entire spectrum of ALS diseases.” Reduced production of MIF was also shown in cell culture with human induced pluripotent stem cells (iPSC) from ALS patients with various genetic causes of the disease. For this purpose, the researchers reprogrammed skin cells back to their original state. From these iPS cell lines, they developed neuronal precursor cells, which then became motor neurons.

Molecular switch boosts protein production

In order to see what happens when the MIF level is raised again, the researchers used a virus-mediated gene shuttle to boost the production of MIF in the nerve cells.The increase in MIF production triggered in this way ensured that less misfolded SOD1 protein was deposited in the human nerve cells.And the mechanism of action also works in the animal model: the virus-mediated introduction of MIF into the central nervous system of the SOD1 mouse model led to an improvement in muscle function, less misfolded SOD1 protein accumulated, inflammatory reactions in the spinal cord decreased, the course of the disease slowed down and the animals survived longer.” Our investigations thus reveal an exciting new treatment option for the incurable neurodegenerative disease ALS,” emphasizes Professor Petri. Clinical studies must now follow to show whether this method only works in cell culture and animal models, or whether it can also be successfully used to treat ALS patients at some point.

Clinics and research institutions in Germany, Israel, Canada and the USA were involved in the project. It was funded by the German Israeli Foundation for Scientific Research and Development (GIF), which has been supporting German-Israeli research cooperation since 1986.

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The original paper “Targeting low levels of MIF expression as a potential therapeutic strategy for ALS” can be found here: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00238-6

https://www.mhh.de/en/presse/mhh-insight/news-detailed-view/new-therapy-option-for-fatal-nerve-disease-als