Study uncovers common trigger across gene mutations that cause ALS

With the help of the Gene Scissors CRISPR and stem cells, researchers from Stockholm University and the UK Dementia Research Institute (UK Dri) at King’s College London have succeeded in identifying a common denominator for different gencutations that all cause the neurological disease. The research shows that as-linked dysfunction occurs in the energy factories of nerve cells, the mitochondria, before the cells show other signs of disease that were not known before. The study was recently published in the scientific journal Nature Communications.

“We show that the nerve cells, which are called motor neurons, who will eventually die, have problems shortly after they have been formed. We saw the earliest sign of problems in the energy factories of the cell, the mitochondria, and also in how they are transported in the nerve cells in the nerve cell in the united king,” ” London.

The research team was able to establish that these problems were common for all mutations caused by, which will be important for future treatments of the disease.

This means that there are common factors that can be aimed at medicines, regardless of the cause of the disease. “

Dr. Eva Hedlund at the University of Stockholm

Reprogrammed cells

The researchers used the Gene Scissors CRISPR/CAS9 to introduce different as-causing mutations in human stem cells, called IPS cells. Motor neurons were produced from this, the nerve cells that are lost in ALS and internurones, nerve cells that are relatively resistant to the disease. These were then analyzed with RNA sequencing with one cells, a method that makes identification of all Messenger-Molecules (mrna) possible in each individual cell and who understand how a certain cell works, how it talks to his neighbors and whether it starts to have problems.

“In the data we have obtained, we identified a common signature of the disease about all as-causing mutations, which were unique to motor neurons and therefore did not arise in resistant neurons,” says Dr. Christoph Schweinguber, first author of the study.

This happened very early and was completely independent of whether the pathogenic mutated proteins (FUs or TDP-43) were in the wrong place in the cell or not.

“Until now it was assumed that it is the change in which the proteins are in the cells, called failure, which first occurs,” says Dr. Marc-David Ruepp.

A groundbreaking discovery

In ALS it is often said that some problems are caused by a loss of function in a protein that is mutated, while other problems arise as a result of the opposite, namely the rise of a new toxic function obtained by the mutation, called “profit function”, but according to Eva Hedlund, it has not always been easy to clarify how it really works and much is known.

“By making different CRISPR mutations in the as-causing Fus-Gene, we have now been able to prove for the first time that most of the mistakes occurring are caused by a new toxic feature of the protein, not by a loss of function,” says Dr. Christoph Schweinguber.

The energy factories of the cells influence

A third discovery was that the transport of mitochondria in the axons, the extensions of the nerve cells where most mitochondria are needed in nerve cells, was radically influenced in the as -lines. This happened independently of whether the disease-causing proteins were in the wrong place in the cell or not.

“A fact that is a problem because there is a great need for these energy factories in the extensions of the nerve cells. Without them, the nerve cells do not have enough energy to communicate well with other cells,” says Dr. Eva Hedlund.

The new discoveries are open to early treatment methods, something that is a continuous work for the research team.

“We try to understand how these early errors occur in the sensitive motor neurons in ALS, and how it influences the energy levels in the cells and their communication and necessary contacts with muscle fibers. We believe that these are important keys to the understanding of why the synapses between motor neurons and muscles are broken in ALS and also about therapies Dr. says Dr. says Dr. Eva Hedlund.