New research on ALS opens up for early treatment

Using the gene scissors CRISPR and stem cells, researchers at Stockholm University and the UK Dementia Research Institute (UK DRI) at King's College London have managed to identify a common denominator for different gene mutations that all cause the neurological disease ALS. The research shows that ALS-linked dysfunction occurs in the energy factories of nerve cells, the mitochondria, before the cells show other signs of disease, which was not previously known. The study was recently published in the scientific journal Nature Communications. "We show that the nerve cells, termed motor neurons, that will eventually die in ALS have problems soon after they are formed. We saw the earliest sign of problems in the cell's energy factories, the mitochondria, and also in how they are transported out into the nerve cells' long processes where there is a great need for them and the energy they produce," says Dr Eva Hedlund at Stockholm University, head of the study together with Dr Marc-David Ruepp at the UK Dementia Research Institute at King's College London. The research team was able to establish that these problems were common to all ALS-caused mutations, which will be important for future treatments of the disease. "This means that there are common factors that could be targeted with drugs, regardless of the cause of the disease," says Dr Eva Hedlund.

Reprogrammed cells

The researchers used the gene scissors CRISPR/Cas9 to introduce various ALS-causing mutations into human stem cells, called iPS cells. From these, motor neurons, the nerve cells that are lost in ALS, and interneurons, nerve cells that are relatively resistant to the disease, were produced. These were then analyzed with single-cell RNA sequencing, a method that enables identification of all messenger molecules (mRNA) in each individual cell and understanding how a particular cell works, how it communicates with its neighbors, and if it starts to have problems. "In the data we obtained, we identified a common disease signature across all ALS-causing mutations, which was unique to motor neurons and thus did not arise in resistant neurons," says Dr Christoph Schweingruber, first author of the study. This happened very early and was completely independent of whether the disease-causing mutated proteins (FUS or TDP-43) were in the wrong place in the cell or not. "Until now, it has been believed that it is the change where the proteins are within the cells, called mislocalization, that occurs first," 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 mutated protein, while others arise due to the emergence of a new toxic function obtained through the mutation, called "gain-of-function." However, according to Eva Hedlund, it has not always been easy to clarify how it really works, and much is still unknown. "By making various CRISPR mutations in the ALS-causing FUS gene, we have now been able to show for the first time that most errors arising are caused by a new toxic property of the protein, not by a loss of function," says Dr Christoph Schweingruber.

Affecting the cells' energy factories

A third discovery was that the transport of mitochondria out into the axons, the extensions of the nerve cells where most mitochondria are needed, was radically affected in the ALS lines. This happened independently of whether the disease-causing proteins were in the wrong place in the cell or not. "A fact that poses 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 properly with other cells," says Dr Eva Hedlund. The new discoveries open up possibilities for early treatment methods, which the research team continues to explore. "We are trying to understand how these early errors occur in the sensitive motor neurons in ALS, how they affect energy levels in the cells and their communication and necessary contacts with muscle fibers. We believe that these are important keys to understanding why the synapses between motor neurons and muscles are broken in ALS and also to identifying new targets for therapies," says Dr Eva Hedlund.

This article was originally published on ScienceDaily Top Health.