New class of highly effective inhibitors protects against neurodegeneration

October 08, 2020

Neurobiologists at Heidelberg University have discovered how a special receptor at neuronal junctions that normally activates a protective genetic programme can lead to nerve cell death when located outside synapses. Their fundamental findings on neurodegenerative processes simultaneously led the researchers at the Interdisciplinary Center for Neurosciences (IZN) to a completely new principle for therapeutic agents. In their experiments on mouse models, they discovered a new class of highly effective inhibitors for protecting nerve cells. As Prof. Dr Hilmar Bading points out, this novel class of drugs opens up - for the first time - perspectives to combat currently untreatable diseases of the nervous system. The results of this research were published in Science.

The research by Prof. Bading and his team is focused on the so-called NMDA receptor. This receptor is an ion channel protein that is activated by a biochemical messenger: the neurotransmitter glutamate. It allows calcium to flow into the cell. The calcium signal sets in motion plasticity processes in the synapse but also propagates into the cell nucleus, where it activates a protective genetic programme. Glutamate-activated NMDA receptors located in the junctions of the nerve cells have a key function in the brain, contributing to learning and memory processes as well as neuroprotection. But the same receptors are also found outside of synapses. These extra-synaptic NMDA receptors pose a threat because their activation can lead to cell death. Normally, however, efficient cellular uptake systems for glutamate make sure that these receptors are not activated and nerve cells remain undamaged.

This situation can change dramatically in the presence of disease. If, for example, parts of the brain are not supplied with sufficient oxygen after a stroke, disruptions in circulation negate the glutamate uptake systems. The glutamate level outside synapses increases, thereby activating the extra-synaptic NMDA receptors. The result is nerve cell damage and death accompanied by restrictions in brain function. Increased glutamate levels outside the synapses occur not only during circulatory disturbances of the brain. "The evidence suggests that the toxic properties of extra-synaptic NMDA receptors play a central role in a number of neurodegenerative diseases," explains Prof. Bading. According to the scientist, this applies, in particular, to Alzheimer's disease and Amyotrophic Lateral Sclerosis with its resulting muscle weakness and muscle wasting as well as retinal degeneration, and possibly even brain damage after infections with viruses or parasites.

While glutamate-activated NMDA receptors inside neuronal junctions help build up a protective shield, outside synapses they change from Dr Jekyll into Mr Hyde. "Understanding why extra-synaptic NMDA receptors lead to nerve cell death is the key to developing neuroprotective therapies," continues Prof. Bading. That is precisely where the Heidelberg researchers are focusing their efforts. In their experiments on mouse models, they were able to demonstrate that the NMDA receptors found outside synapses form a type of "death complex" with another ion channel protein. This protein, called TRPM4, has a variety of functions in the body, with roles in the cardiovascular system and immune responses. According to the latest findings by Hilmar Bading and his team of researchers, TRPM4 confers toxic properties on extra-synaptic NMDA receptors.

Using molecular and protein biochemical methods, the scientists identified the contact surfaces of the two interacting proteins. With this knowledge, they used a structure-based search to identify substances that might disrupt this very bond, thereby dismantling and inactivating the "death complex". This new class of inhibitors - which the Heidelberg researchers call "interface inhibitors" because they disrupt the bond formed at the contact surfaces between the extra-synaptic NMDA receptors and TRPM4 - proved to be extremely effective protectors of nerve cells. "We're working with a completely new principle for therapeutic agents here. The interface inhibitors give us a tool that can selectively remove the toxic properties of extra-synaptic NMDA receptors," explains Prof. Bading.

Prof. Bading and his team were already able to demonstrate the efficacy of the new inhibitors in mouse models of stroke or retinal degeneration. According to the Heidelberg researcher, there is good reason to hope that such interface inhibitors - administered orally as broad-spectrum neuroprotectants - offer treatment options for currently untreatable neurodegenerative diseases. "However, their possible approval as pharmaceutical drugs for human use will take several more years because the new substances must first successfully pass through a number of preclinical and clinical testing phases."
-end-
The research was funded by the European Research Council (ERC) and the German Research Foundation (DFG).

University of Heidelberg

Related Nerve Cells Articles from Brightsurf:

Nerve cells let others "listen in"
How many ''listeners'' a nerve cell has in the brain is strictly regulated.

Nerve cells with energy saving program
Thanks to a metabolic adjustment, the cells can remain functional despite damage to the mitochondria.

Why developing nerve cells can take a wrong turn
Loss of ubiquitin-conjugating enzyme leads to impediment in growth of nerve cells / Link found between cellular machineries of protein degradation and regulation of the epigenetic landscape in human embryonic stem cells

Unique fingerprint: What makes nerve cells unmistakable?
Protein variations that result from the process of alternative splicing control the identity and function of nerve cells in the brain.

Ragweed compounds could protect nerve cells from Alzheimer's
As spring arrives in the northern hemisphere, many people are cursing ragweed, a primary culprit in seasonal allergies.

Fooling nerve cells into acting normal
In a new study, scientists at the University of Missouri have discovered that a neuron's own electrical signal, or voltage, can indicate whether the neuron is functioning normally.

How nerve cells control misfolded proteins
Researchers have identified a protein complex that marks misfolded proteins, stops them from interacting with other proteins in the cell and directs them towards disposal.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Research confirms nerve cells made from skin cells are a valid lab model for studying disease
Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

Bees can count with just four nerve cells in their brains
Bees can solve seemingly clever counting tasks with very small numbers of nerve cells in their brains, according to researchers at Queen Mary University of London.

Read More: Nerve Cells News and Nerve Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.