New approach may prevent neurotoxic protein aggregates in ALS

Researchers at Goethe University, Johannes Gutenberg University Mainz and Kiel University discover possible method for preventing proteinaggregates – Cluster4future Proxidugs Research project.

If the protein TDP-43 is defective in a nerve cell, this can form neurotoxic aggregates, which is the cause of the neurodegenerative disease amyotrophe lateral sclerosis (ALS). Nerve cells are also damaged by TDP-43 in Alzheimer’s dementia. A research team led by Goethe University has now succeeded in preventing these aggregates by manipulating the protein so that it is transported to the cell’s own repair system. The study was conducted as part of the Cluster4Future Proxidrugs. The cluster is investigating a new class of medicines that reprogram cellular systems to make disease-relevant proteins harmless.

2500 new cases of amyotrophe lateral sclerosis are diagnosed every year, making it a relatively rare but very serious nervous system disease. A remedy is not yet possible. As the motor neurons in the brain and the spinal cord that is responsible for voluntary muscle control slowly destroys. The result is progressive muscle paralysis, so that many patients remain wheelchair dependent. As the disease progresses, individuals find it increasingly difficult to speak, swallow and breathe.

In as collecting poorly soluble proteinaggregates in motor neurons. These aggregates, among other things, consists of TDP-43, which plays various critical roles in cellular RNA metabolism. While in healthy cells TDP-43 is mainly found in soluble form in the cell nucleus, it forms poorly soluble aggregates that mainly accumulate outside the cell nucleon. This means that TDP-43 loses its functionality, and ultimately leads to the death of the motor neurons.

As part of the Cluster4Future Proxidrugs funded by the Federal Ministry of Education and Research (Germany), researchers from the universities of Frankfurt, Mainz and Kiel have now discovered a way to prevent the formation of harmful TDP-43 aggregates in cultivated cells. To do this, scientists led by Kristina Wagner, Dr. Jan Keiten-Schmitz and Professor Stefan Müller from the Institute of Biochemistry II at Goethe University exposed cells to stress, for example by raising the temperature or using a chemical substance. As a result, some TDP-43 was released from the cell nucleus in the cytosol, where it accumulated in so-called voltage pellets.

The formation of such stress pellets is a normal process and serves the cell as a temporary protective space for proteins so that they are immediately available for the cell as soon as the stress has disappeared. However, if TDP-43 is mutated, because it is in the cells of many ALS patients, the stress pellets will continue to exist, solid and damage the neurons. “

Dr. Jan Keiten-Schmitz

The scientists successfully prevented TDP-43 from leaving the cell nucleus under stress by connecting it with the “roadside assistance”-a protein called TDP-43 to a cellular “mechanic”, the so-called nuclear bodies. “As a result, TDP -43 remains soluble and the nuclear bodies – such as a technician – ensure that harmful forms of TDP -43 are restored or broken down by the cellular recycling system,” says Kristina Wagner, a first author of the study. Insoluble protein aggregates that damage or even kill cells would therefore be prevented in the first place.

The team of researchers is now looking for future drug candidates in the form of chemical connections that bring Sumo and TDP-43 together. Proxidrugs Principal Investigator Müller explains: “Our experiments with the cell culture offer a first proof-of-principle: this route can help cells to limit the disease-promoting TDP-43 aggregates. Even if the road to the development of a possible drug is still treatment, is still treatment of treatment, treatment of treatment as still treatment, is still treatment of treatment as still treatment as still treatment as still treatment, Dementia (FTD) and in about half of all patients of Alzheimer’s.