Basic research for the benefit of ALS patients
By understanding why certain nerve cells and the muscles they control are resistant to fading in the deadly disease ALS, it is possible to create new possibilities for treatments. Researchers at Stockholm University are now trying to identify and transfer the properties of these resistant nerve cells.
Eva Hedlund has been a professor of neurochemistry at Stockholm University since 1 November 2021. She leads a research team that engages in basic research with a medical benefit aspect, finding new treatments for patients with severe neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis) and SMA (spinal muscle atrophy). Common to these diseases is that the motor nerve cells (motor neurons) and their long protrusions (nerve pathways), which regulate all our will-controlled movements, wither and then also the muscles. Eventually, the patients become paralyzed. -
"We have a focus on ALS and the challenge is to map this very complex disease at the cellular level to understand how it can arise and develop and thus how one could intervene in the disease processes to help the affected patients," says Eva Hedlund.
Three major issues are being studied
There are mainly three major issues that her group focuses on. The first is how different hereditary ALS-causing gene mutations lead to degeneration of motor neurons and whether there are similarities with sporadic disease. Another question is why some motor neurons are so resistant to ALS when most of their similar neighbors are lost to the disease. Third, researchers are studying the causes of motor neurons and muscles losing contact with each other early in the pathological process.
"Based on these issues, we design experiments and hope that the results in the future will guide us towards new treatments that are applicable to ALS," says Eva Hedlund.
Coupling is destroyed and muscles wither
The motor neurons that Eva Hedlund and her team study have their cell bodies in our central nervous system (in the brainstem and spinal cord) but send out their long protrusions, axons, throughout the body to form synapses with the muscles and thus control all our skeletal muscles and thus all voluntary movements. The axons can extend up to one meter in the body to reach the muscles of the fingers and toes. If the connection, the synapse between the motor neuron's axon and the muscle, disappears, the muscle can not be used. In ALS and SMA, this is exactly what happens, that the synapse, between the motor neuron and muscles, is destroyed, with the result that the axon breaks down and the muscle withers.
"ALS patients eventually become completely paralyzed, so they can not move, swallow or take a deep breath. However, the motor neurons that control the eye muscles are so resistant to the disease that patients, even in the final stages, can move their eyes. Therefore, tracking devices are used that interpret patients' eye movements so that they can communicate with their surroundings. I became early curious about what makes certain motor neurons so resistant and thought that if we can understand this we can find ways to protect even sensitive motor neurons," says Eva Hedlund.
Analysis of large amounts of data
Human motor neurons derived from stem cells. Photo: Christoph Schweingruber
The research is both experimentally intensive, including the cultivation of human motor neurons derived from stem cells, but also includes analysis of large amounts of data. The lab studies, among other things, how the introduction of ALS-causing mutations, through the use of the CRISPR / Cas9 gene scissors, affects all messenger molecules, mRNA, in various motor neurons and thus their function.
Eva Hedlund's research has successfully shown that it is possible to use the properties of resistant motor neurons to strengthen weaker motor neurons that easily degenerate. In several studies, they have introduced factors from resistant motor neurons via gene therapy and shown that cultured human motor neurons from ALS and SMA patients have increased resistance and that mouse models with ALS or SMA survive the diseases much longer.
International research award
This insight has led to Eva Hedlund and her colleagues being awarded the Norwegian prize The Olav Thon Foundation's International Research Award. The prize money of NOK 10 million goes to a research project with the aim of better understanding and applying aspects related to the motor neurons' different sensitivity in ALS. Earlier this year, she was also awarded a prestigious international prize from the Radala Foundation for ALS Research in Switzerland.
New opportunities at Stockholm University
Eva Hedlund has been working at Stockholm University for just over a year. Before that, she had built up a research group at Karolinska Institutet (KI). Coming to Stockholm University has opened up new avenues for interdisciplinary dialogue, according to Eva Hedlund.
"I have always enjoyed KI and still have my contacts there, but the move to Stockholm University is incredibly fun, in that we can talk more multidisciplinary with biochemists, biophysicists, physicists and researchers who have completely different model systems and angles, as well as that it opens for more collaborations across institutional boundaries."
What is current in research on ALS and neurodegenerative diseases?
"In 10 percent of all ALS cases, the disease is clearly inherited and we now usually know which gene mutation causes the disease, even though we do not yet understand why motor neurons are selectively sensitive and lost. In the case of these cases of ALS with a clear genetic cause, much exciting is happening on the research front, both about how mutated pathogenic genes mechanistically cause pathological changes and about how clinical trials of antisense oligos (ASOs) to lower the levels of toxic gene products," says Eva Hedlund.
Incorrect communication between the cells
According to her, sporadic disease, which accounts for 90 percent of all ALS patients, is an even greater challenge. Although one has begun to understand that genetics is a major contributing factor to the onset of the disease, it seems very complex and is not yet understandable. It is now important to understand whether sporadic disease and inherited gene mutations lead to motor neuron death in different or similar ways and thus must be treated individually or as a group. Eva Hedlund's research group studies this with the help of genetic scissors, and RNA sequencing of individual human motor neurons. They also examine how individual cells and their axons respond to disease events that are either sporadic or inherited.
Eva Hedlund and her colleagues have developed several techniques for studying mRNA in the axons and cell bodies of motor neurons, and they are also building new advanced human cell culture models to investigate how muscles and motor neurons talk to each other.
"We believe that the early destruction of the synapse in ALS is due to an incorrect communication between the cells and that an identification of these signals can provide a great piece of the puzzle for understanding ALS," says Eva Hedlund.
Last updated: March 16, 2022
Source: Department of Biochemistry and Biophysics