A new mechanism has been identified behind the toxicity exercised on neurons in the brain by the mutant protein responsible for Huntington Disease, one of the most serious hereditary disorders that lead to the degeneration of the central nervous system. In the toxicity of the altered form of Huntingtin, which is the name of the protein in question able to trigger the devastating disease, a fundamental role is played by a "team" of enzymes that becomes mobilised in response to its presence, contributing to the activation of one of the main "guardians" of cell integrity and the genome, factor p53.

For p53, protection may also sometimes mean bringing about cell suicide (apoptosis) and it is in this way that mutant Huntingtin causes the death of the neurons. Thanks to this achievement, the proteins that cause brain cells to undertake this journey of no return could become the point of attack for treatment of the disease.

The discovery was made by a team of scientists from the CIB National Laboratory (LNCIB) at Trieste Area Science Park and the University of Trieste, headed by Giannino Del Sal, in collaboration with SISSA (International School for Advanced Studies) in Trieste and the Amedeo Avogadro University of Eastern Piedmont. It was published online this week by the authoritative scientific journal Proceedings of the National Academy of Sciences.

How does p53, or rather that which has been defined as one of the most formidable "guardians" of the genome and also one of the most important tumour suppressors, come into play? Del Sal explains: "In normal conditions, p53 is present in the cells in a form that we could describe as 'dormant' and at very low levels. However, this factor is activated and accumulated at the slightest sign of stress thanks to the combined and complex action of different proteins: enzymes that detect problems and damage and act on p53, modifying it with the addition of particular chemical groups and even making it undergo a conformational change. All this is done in order to make it active or more active, depending on the circumstances, and capable of initiating the gene expression programme through which the cell reacts to the situation at hand."

Scientific discussions with Francesca Persichetti, Associate Professor of Genetics at the Amedeo Avogadro University of Eastern Piedmont and coordinator of a research programme into Huntingdon Disease in the Neurobiology Sector of SISSA in Trieste, led to the idea of a collaboration to make use of the experience and scientific knowledge acquired by Del Sal on p53 in order to seek a better understanding of the molecular events linked to Huntingdon Disease.

"It is calculated that between 5 and 10 people in every 100,000 today display symptoms of this terrible neurodegenerative disorder, caused by the mutation of a single gene", emphasises Persichetti. "There is currently no treatment available that can halt the inexorable progress of the disease or its onset." Del Sal continues: "However, the workings of the molecular mechanism that we have highlighted reveal a number of potential targets, possible points of attack for the development of new therapeutic strategies."

The research was carried out thanks to the support of Telethon.