Charcot’s disease: mechanism behind genetic form of disease has been discovered

Stratsbourg We have discovered the biological mechanism underlying the most common genetic forms of two neurodegenerative diseases: ALS (amyotrophic lateral sclerosis ) and frontotemporal dementia.

This new knowledge could help in the development of future therapeutic targets. Our results have just been published in the journal Science.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal neurodegenerative disease. Life expectancy after diagnosis is estimated at three years, and it affects approximately 6,000 people in France.

The disease results from the progressive destruction of motor neurons, the neurons responsible for controlling muscles. The death of these neurons causes the characteristic motor disorders of the disease (complete paralysis of the muscles in the arms, legs, and throat, leading to a gradual inability to walk, eat, speak, or even breathe).

The causes of this disease are highly varied. 10 per cent of ALS cases are genetic in origin, while 90 per cent are sporadic, meaning they have no identified cause. In the case of the genetic form, the most frequent cause is a defect in a specific gene (C9ORF72) that triggers the synthesis of toxic proteins, which lead to the death of motor neurons.

This gene contains abnormally repeated sequences that carry erroneous genetic information. The translation of this genetic defect leads to the production of aberrant (because they should not exist) and neurotoxic proteins.

Our discovery has allowed us to understand that this synthesis of toxic proteins is solely responsible for the pathology. By specifically blocking the production of these proteins, we have succeeded in halting the degeneration of motor neurons and thus preventing the onset of the disease.

We first reproduced, in vitro, the synthesis of toxic proteins responsible for the death of motor neurons. These proteins are produced by the cell’s ribosome from the C9ORF72 gene. In all cells, proteins are produced by ribosomes. Once bound, the ribosome reads the RNA and translates it into protein. If the ribosome does not recognise this particular site, protein synthesis is impossible.

Through these experiments, we were able to identify the ribosome’s starting site. By introducing a simple point mutation (replacing a single base with another) at this site in the C9ORF72 gene, the synthesis of toxic proteins is completely shut down. We confirmed these results in cells and then in mice.

Our next step involved using this knowledge to correct the C9ORF72 gene in motor neurons from ALS patients (cultured in the laboratory). Using the CRISPR-Cas9 “molecular scissors” technology, the ribosome’s starting site was modified; this single modification was sufficient to completely shut down toxic synthesis in these motor neurons and restore their lifespan.

ALS, like most neurodegenerative diseases, is triggered by multifactorial causes. This makes treating these conditions extremely complex. Our research has characterised the molecular mechanism that triggers the disease and led to the precise identification of the cause of ALS in the most common form, which accounts for approximately 8 per cent of cases.