identification of a key pathway that triggers neurodegeneration

In France, each year, there are approximately 2.7 new cases of amyotrophic lateral sclerosis (ALS) per 100,000 inhabitants, according to Civil hospices of Lyon. This pathology, better known as Charcot disease, is characterized by progressive paralysis with a fatal outcome.after 3 to 5 years of development on average“, according to the National Institute of Health and Medical Research (Inserm).

The role of TDP-43 and CHMP7 proteins in Charcot disease

For the moment, there is no curative treatment. Inserm also indicates that “it is still very difficult to precisely establish the mechanisms that initiate and maintain the neuronal degeneration involved in ALS”. But research is moving forward. Researchers have just identified a key mechanism in the triggering of this pathology. Their work was published in the journal ​​Neuron.

In people with Charcot disease, the TDP-43 protein accumulates in the cytoplasm of motor neurons – instead of being only concentrated in their nucleus – which harms their functioning and causes neuronal degeneration. This accumulation in the wrong place is a sign of ALS already known to scientists.

“At the moment when you [découvrez] an ALS patient and you see the TDP-43 protein accumulated in the cytoplasm, it’s like [si vous arrivez] at the accident site with all the cars already [cabossées]but this is not the triggering event“, indicates Gene Yeo, one of the authors, in a communiqué.

The whole challenge of this work was therefore to find the cause(s) of the accident! The scientists’ first discovery was that another protein called CHMP7 – normally found in the cytoplasm of motor neurons – accumulates in the nucleus. This poor positioning of CHMP7 disrupts the transport of TDP-43, which explains its poor positioning.

A first step therefore, but the scientists’ investigation did not stop there. They then sought to understand what caused the accumulation of CHMP7 in the nucleus of motor neurons. To do this, they studied the proteins linked to RiboNucleic Acids (RNA)molecules carrying genetic information. Among the 55 proteins identified as being able to influence the accumulation of CHMP7, the scientists selected 23 linked to ALS. Next, they blocked the action of each of these proteins to see if this led to an increase in CHMP7 in the motor neuron nucleus.

Protein mispositioning due to SmD1

With further experiments, the scientists found that depletion of one of the 23 proteins, called SmD1, affected the level of CHMP7 and promoted its accumulation in the nucleus of motor neurons. In other words, when the role of SmD1 or this protein is no longer produced, this causes a dysfunction of CHMP7, which then impacts TDP-43.

Conversely, when the researchers stimulated the expression of SmD1, the effects were beneficial:

• The CHMP7 protein was placed in the cytoplasm of motor neurons
• TDP-43 remained concentrated in their motor neuron nuclei.

Thus, this good positioning of each protein prevented degeneration.

The SmD1 protein is already being targeted by treatments for spinal muscular atrophy, another neurodegenerative disorder. “One of them, risdiplam, is a small molecule compound that enhances the splicing and expression of SMN2, a gene closely related to the SMN1 gene that becomes dysfunctional in ALS”, underlines Gene Yeo.

The authors want to continue their research to see if treatments like risdiplam could be effective for Charcot disease. In France, around 5,000 to 7,000 patients are currently suffering from this pathology, according to the CHU de Toulouse.