The new approach can prevent neurotoxic proteins in ALS

Scientists from Goethe University, Johannes Gutenberg University Mainz and Kiel University discover a possible method of preventing protein aggregates – the Cluster4future Proxidrugs research project.

If the TDP-43 protein is defective inside the nerve cell, it can create neurotoxic aggregates that cause a neurodegenerative lateral nitrogenic sclerosis (ALS). Nerve cells are also damaged by TDP-43 in Alzheimer’s dementia. The research team led by the Goethe University managed to prevent these aggregates by manipulating protein so that it is transported to its own cell repair system. The study was conducted as part of the Cluster4future napkin services. The cluster examines a new class of drugs that will reprogram cell systems to make proteins associated with harmless disease.

2,500 new cases of atrophic lateral sclerosis are diagnosed each year, which makes it relatively rare, but a very serious disease nervous system. The medicine is not yet possible. ALS is slowly destroying motor neurons in the brain and spinal cord responsible for voluntary muscle control. The result is progressive muscle paralysis, leaving many patients in a wheelchair. As the disease progresses, units are increasingly difficult to speak, swallow and breathe.

In ALS, poorly soluble protein aggregates accumulate in motor neurons. Among other proteins, these aggregates consist of TDP-43, which plays various critical roles in RNA cell metabolism. While in healthy TDP-43 cells it occurs mainly in a soluble form in the cell nucleus, in patients with ALS it creates poorly soluble aggregates that mainly accumulate outside the cell nucleus. This means that TDP-43 loses its functionality and ultimately leads to the death of motor neurons.

As part of the Cluster4future service services financed by the Federal Ministry of Education and Research (Germany), scientists from universities from Frankfurt, Moginz and Kiel have now discovered a way to prevent the creation of harmful TDP-43 aggregates in bred cells. To this end, scientists led by Kristina Wagner, dr Jan Keiten-Schmitz and Professor Stefan Müller from the Institute of Biochemistry II at Goethe University exposed the cells to stress, for example by increasing temperature or the use of a chemical. As a result, some TDP-43 was released from the cell nucleus to cytosol, where it accumulated in so-called stress granules.

Creating such stress granules is a normal process and serves the cell as a temporary protective space for proteins, thanks to which they are immediately available to the cell after stress. However, if the TDP-43 is mutated, as in the cells of many ALS patients, stress granules persist, solidify and eventually damage neurons. “

Dr Jan Keiten-Schmitz

Scientists successfully prevented the TDP-43 to leave the cell nucleus under stress by connecting it with “roadside help” with a white cell called Sumo-where directed TDP-43 to the cellular “mechanic”, so-called nuclear bodies. “As a result, TDP -43 remains soluble, and nuclear bodies – like a mechanic – ensure that the harmful forms of TDP -43 are restored or unfolded by the cellular recycling system,” says Kristina Wagner, the first author of the study. Non -reinforced protein aggregates, whose damage and even killing of cells could not create the formation above all.

A team of scientists is now looking for future drug candidates in the form of chemical compounds that combine SUMO and TDP-43. The main service researcher Müller explains: “Our experiments from cell breeding are the first proof of Principle: this trail can help cells to limit TDP -43 aggregates. Fire -legged dementia (FTD) and about half of all Alzheimer patients.”