Thanks to deep mutagenesis, Spanish scientists have discovered that, contrary to what we thought, the protein aggregation that we see in patients with amyotrophic lateral sclerosis (ALS) actually protects the cells.
Amyotrophic lateral sclerosis (ALS), better known as Charcot’s disease, is a serious and disabling degenerative disease. This incurable nervous system affliction attacks nerve cells in the brain and spinal cord, leading to loss of muscle control. It also affects speech and swallowing. The diagnosis takes place between the ages of 50 and 70 and, generally, three to five years later, the outcome is fatal, most often because of the attack of the respiratory muscles. At present, we know that ALS is familial in 10% of patients. In these cases, a genetic origin is suspected. When the disease affects people without genetic risk, it is said to be sporadic. “These cases are probably linked to the random (and not transmitted) mutation of a causal gene or of one or more susceptibility genes (which would increase the risk of occurrence of the disease)”, notes Inserm on its website. Concerning the environment, tobacco, high-level sport, pesticides, heavy metals and the BMAA cyanotoxin found in certain algae are suspected to be risk factors.
And while scientists have long known that specific protein aggregates are hallmarks of the disease, they still don’t know if they really cause it. In order to better answer this question, in Spain, researchers from the Center for Genomic Regulation (CRG) and the Institute of Bioengineering of Catalonia (IBEC) have implemented a new method called deep mutagenesis. They discovered that contrary to many hypotheses, the protein aggregation in question was not a bad thing: it would in fact protect the cells, as revealed a press release published on September 20 on the CRG website.
For their research, the scientists focused on TDP-43, a protein that aggregates in the motor neurons of almost all ALS patients. They made more than 50,000 mutations of TDP-43 and studied their toxicity in yeast cells. They were thus able to observe that the mutant forms which aggregated were less toxic than other versions of the protein which instead formed unusual liquid species in the cells.
“The opposite of what we expected”
“This is exactly the opposite of what we expected”, explains Professor Ben Lehner. Thus, the aggregation of TDP-43 would protect the cells. This discovery completely changes our understanding of the disease and opens the door to completely different therapeutic approaches.
“By studying all the possible mutations of a protein, we have a much more reliable way of understanding toxicity and we are delighted to now be studying many more proteins implicated in neurodegenerative diseases”, welcomes Benedetta Bolognesi, researcher at IBEC, alumnus of the CRG and main author of this article.
And the press release concludes: “it remains to be determined whether the aggregation of TDP-43 also protects mammalian cells and neurons, which Bolognesi is working on, but if so, it means that we will have to change completely our way of treating ALS if we are to achieve meaningful effects.”
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