MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients' Cells

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Harhouri, Karim | Cau, Pierre | Casey, Frank | Guedenon, Koffi Mawuse | Doubaj, Yassamine | van Maldergem, Lionel | Mejia-Baltodano, Gerardo | Bartoli, Catherine | de Sandre-Giovannoli, Annachiara | Levy, Nicolas

Edité par CCSD ; MDPI -

International audience. Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A increment 50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named ``HGPS-like `` patients. They produce progerin and/or other truncated prelamin A isoforms ( increment 35 and increment 90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients' cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS.

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