Unique molecular mechanism protects neurons in progeria patients

Progeria is an extremely rare genetic disease, which induces premature and accelerated ageing in patients. The mutation causing the syndrome affects the LMNA gene that encodes proteins called “lamins” A and C.

Lamins are involved in maintaining the structure of the nuclear membrane. They determine nuclear shape and stiffness and allow communications within the cells. In the case of progeria, lamin A is defective. In its mutated form, it becomes toxic and damages the membranes of the nucleus, disrupts the message and causes accelerated ageing of cells. In 2003 the research team of Dr. Nicolas Levy in Marseille identified the origin of this disease.

The development of this syndrome is rapid: it is estimated that each year, affected children age by more than ten years, leading to their premature death between 13 and 16 years. This accelerated ageing affects most tissues: skin, blood vessels, heart, bones or muscles. Very quickly, patients suffer from muscular and skeletal disorders, stunted growth (their size does not exceed 110 cm for a weight of 15 kg). In contrast, their cognitive abilities are usually not affected. This has always been considered a surprising phenomenon, given the overall disease involvement to which these patients are subjected.

One of the studies of Xavier Nissan et al. in their progeria project showed a unique molecular mechanism that specifically protects neurons in patients with Hutchinson-Gilford progeria syndrome from the defective prelamin A processing.

Skin cells sampled from patients with progeria were induced into pluripotency then differentiated into mature nerve cells. Tuj1 markers highlight nerve cells in green; other markers highlight DNA in blue. Lamin A, if present, would appear in red; the protein is however completely absent in this cell view. 
Copyright: Xavier Nissan, I-Stem 

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The strategy at I-Stem

Recently two phase II clinical trials were initiated by treating HGPS patients with Farnesyltransferase inhibitors (FTIs) and/or the combination of Zoledronate and Pravastatin to prevent or delay the gravest infringements of the disease. Although these two studies have produced promising results, as well as in vitro and in vivo, there is currently no cure for HGPS patients.

In collaboration with Professor Nicolas Lévy, the I-Stem team has generated induced pluripotent stem cells from progeria patients’ cells. Thanks to this unlimited and standardized biological resource they are preparing a high throughput screening campaign of pharmacological compounds in order to identify new treatments of this disease.