Progéria : researchers inhibit accelerated aging
Published the 03.07.2017 at 09h24
disease génétiquemaladies raresAFM-Telethon
The progéria is a genetic disease that affects the ageing of the body.
One birth in 10 to 20 million are affected by this pathology.
The LMNA mutation causes the accumulation of the progérine in the nucleus of cells. This protein is toxic.
Accelerated aging causes the premature death of the patients. On average, they die at about age 14.
No treatment is currently available to combat the disease.
The molecule discovered by professor Nicolas Lévy can inhibit the production of progérine and allows its degradation by the body.
They are children and old men at the time. Not even 12 years old, these young patients have all the signs of aging with advanced hair loss, cardiovascular problems, deep wrinkles… The evil that reaches them is very rare. The progéria affects only one birth in 10 million to 20 million. In the world, a few hundred patients living with this genetic disease.
So far, medical research does not abandon these patients to life expectancy is very short – 14 years on average. At the university of Aix-Marseille, a team of Inserm, with the support of the AFM Telethon. And she gets results.
On 3 July, in EMBO Molecular Medicine, a new track therapeutic sketch. The study describes the discovery of a drug able to inhibit strongly the evolution of the progéria. Explanations with the main author of this work, the Pr Nicolas Lévy.
An abnormal accumulation
At the origin of the progéria, a truncated protein and are toxic to the body. The progérine is normally produced only at an advanced age. But because of a mutation in the gene LMNA, this protein accumulates in the nucleus of cells. “Aging is very similar to that seen in the elderly or very elderly,” says professor Lévy.
This geneticist is at the origin of the discovery of the gene that causes the syndrome of Hutchinson-Gilford (see box). It is also the one who understood how the pathology induces the accelerated aging.
The progérine is not degraded by the cells as it should. “It is accumulated and entirely sequestered in the interior of another protein in the cell nucleus, blocking its access to pathways of degradation,” says the head of the department of medical Genetics at the hospital of la Timone (Marseille).
Pr Nicolas Lévy, geneticist : “The problem pathology of this disease, it is the accumulation of an abnormal protein, which is highly toxic, in the nucleus of cells. “
Action at two levels
The discovery of the drug which target this disease occurred almost by accident. While they were working on the mechanisms of progéria, scientists have tested a molecule so new that it does not yet have a name. Code : MG132. It is an inhibitor of the proteasome, some of which appear in multiple myeloma.
This class of drugs blocks the action of cellular complexes involved in the degradation of proteins. It was, therefore, expected to cause accumulation worsened progérine in the cells of patients. But the opposite phenomenon occurred. “Surprisingly, we obtained a quasi-suppression of the protein to the nucleus of the cell “, recalls Nicolas Lévy.
It is by investigating the reasons of this event as scientists have understood. MG132 is on two levels on the progérine. First, the molecule that “inhibits very strongly the production of the protérine,” says the geneticist. It accumulates less in the cells and causes less breakage of DNA.
But the effect does not stop there. The treatment also promotes the elimination of the progérine, up here it’s impossible. The same observation is made during the laboratory tests, carried out on cells of different tissues to the patients. “In our mouse model, we have obtained the same effect on the reduction of the amount of protein under the effect of this molecule “, adds Nicolas Lévy.
Pr Nicolas Lévy : “It is both a discovery related to the mechanism of the toxic protein, and the discovery of a family of molecules significantly less toxic. “