Comprehensive coverage

Searching for the genetic roots of ALS in new territories

"There is currently no cure for ALS, and the available treatments succeed, at most, in slowing down the spread of the disease a little. According to Prof. Eran Hornstein from the Weizmann Institute: "In the research we conducted we did indeed measure the levels of miR-218 in the brain and spinal cord, but we hope to develop a means to detect its level in body fluids (blood and spinal fluid) or in other routine clinical tests, so that it will be possible to diagnose the disease at an early stage. Also, it may be possible in the future to treat patients with miR-218 substitutes, to prevent nerve damage or even restore nerve function."

MRI scan of an ALS patient. Source: Frank Gaillard, Wikimedia.
MRI scan of an ALS patient. Source: Frank Gaillard, Wikimedia.

Prof. Eran Hornstein's research group, from the Department of Molecular Genetics at the Weizmann Institute of Science, focuses on the study of amyotrophic lateral sclerosis (ALS) - a terminal degenerative disease that damages the nerve cells that control muscle function. Recently, researchers took another step towards finding the genetic roots of this incurable disease. Following the new discoveries, we met with Prof. Hornstein for a conversation to hear what makes his laboratory's approach to the disease unique.

How did you manage to identify genes involved in the onset of ALS?

"The popular opinion is that ALS is caused by a genetic factor. However, the most common cause of the disease is not a defect in the protein-coding gene, but a defect in the non-protein-coding gene, in which there is a segment that repeats itself over and over again. 97% of the genome are genes that do not code for proteins, but for scientists this is largely uncharted territory, as it is difficult to define the consequences of a mutation (sequence change) in those vast territories of the genome where there are no instructions for protein production. As a focused work approach and different from the usual, we decided to look for genes that are expressed only in the motor nerve cells, that is, genes that are expressed specifically for the diseased cells."

In other words, you started by asking why ALS only affects motor neurons.

"True, if we can identify genes that are expressed only in these specific nerve cells, it may be possible to make significant progress in finding the cause of the disease. This approach turned out to be successful: we identified a gene that does not code for a protein that is transcribed into microRNA molecules called miR-218. These tiny molecules have control roles: they weaken gene expression and the protein production process at different stages."

You discovered a microRNA that is only expressed in motor neurons, but how does it relate to disease?

"In a new study recently reported in the scientific journal Science Translational Medicine, we worked with tissues from people with ALS and were able to show that there is a decrease in the expression of miR-218 in these patients, compared to healthy people. This was an important finding that encouraged us to test whether miR-218 has a role in the disease.

"In genetic tests on thousands of patients and tens of thousands of healthy people, we identified some rare mutations in the miR-218 gene in ALS patients. This interesting finding supports that the mutations are involved in the development of the disease. We later discovered that these mutations make miR-218 less accessible for cleavage by Dicer, a protein whose activity is essential for microRNA maturation and activity. In addition, Dicer activity decreases in the motor neuron as a whole in ALS patients, apparently as a result of the disrupted metabolism of the diseased cell. That is, there is a broad decrease in the activity of Dicer, and in addition there is a decrease in the ability of miR-218 to recruit Dicer. We also found that control of dozens of miR-218 messenger RNA targets is disrupted when miR-218 is deficient.

"Next, we intend to engineer mice so that they express the genetic mutations we discovered in miR-218, and then examine whether they develop the disease."

97% of the genome are genes that do not code for proteins, but for scientists this is largely uncharted territory, as it is difficult to define the consequences of a mutation in those vast territories of the genome where there are no instructions for protein production."

Prof. Eran Hornstein. Which genes are involved in the development of ALS disease? Photo: Weizmann Institute Spokesperson
Prof. Eran Hornstein. Which genes are involved in the development of ALS disease? Photo: Weizmann Institute Spokesperson

Have you discovered what miR-218 does in normal motor neurons - and what goes wrong in ALS?

"We discovered that miR-218 plays a crucial role in defining the electrical properties of motor neurons. These nerve cells transmit messages to the muscles through electrical signals - and this is one of the functions that are damaged in ALS. miR-218 regulates the production of proteins that are responsible for the opening and closing of ion channels in nerve cells, which transmit electrical signals. We hypothesize that lower than normal levels of miR-218 are associated with neuronal cell dysfunction that worsens with human aging."

How will the current research affect the diagnosis of the disease and its treatment?

"There is currently no cure for ALS, and the available treatments succeed, at most, in slowing down the spread of the disease a little. In the research we conducted, we did indeed measure the levels of miR-218 in the brain and spinal cord, but we hope to develop a means to detect its level in body fluids (blood and spinal fluid) or in other routine clinical tests, so that the disease can be diagnosed at an early stage. Also, it may be possible in the future to treat patients with miR-218 substitutes, to prevent nerve damage or even restore nerve function."

One in 400 people will get ALS. The average age at which the disease starts is 60, but there are also very young patients.

for scientific research

3 תגובות

  1. Doctors normally do not know how to read statistics correctly (I am also a doctor).
    The incidence of ALS is 10-20 people per million people *every year*.
    That means 1 in 100,000 to 1 in 50,000 *every year*.
    With a life expectancy of about 5 years (say), then one in every 10,000 people has ALS at any point in time.
    But over a lifetime, that means 800 to 1600 (10-20 times the lifespan, roughly 80 years) out of every million people will be diagnosed, which is 1 in 1250 or 1 in 625. The numbers are not exact and indeed some talk about 1 in 500 or 1 in 400.

    Regarding "David's son" it depends on whether your father had a gene that causes the disease exclusively, which is around a 4-5 percent chance, then the risk of passing it on to you is 50%, or if he did not have an exclusive gene, then your chance of getting sick is not significantly higher than the rest of the population.

Leave a Reply

Email will not be published. Required fields are marked *

This site uses Akismat to prevent spam messages. Click here to learn how your response data is processed.