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

Karim Harhouri,Yassamine Doubaj,Lionel Van Maldergem,Nicolas Lévy,Catherine Bartoli,Koffi Mawuse Guedenon,Pierre Cau,Frank Casey,Annachiara De Sandre-Giovannoli,Gerardo Mejia-Baltodano

doi:10.3390/cells11040610

Abstract

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 ∆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 (∆35 and ∆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.

Highlights

We demonstrated that proteasome inhibitor MG132, not yet FDA/EMA-approved, induces significant progerin inhibition through a dual action: MG132 reduces progerin production through the downregulation of SRSF-1 and SRSF5, controlling prelamin A mRNA aberrant splicing, and induces progerin degradation through macroautophagy
Hutchinson-Gilford Progeria Syndrome (HGPS)-like patients were previously reported to present distinct aberrant splicing patterns of prelamin A pre-mRNAs due to mutations located around the exon 11 donor splice site (Figure 1B,C) [16]
Patient HGPS-L1 [16] carrying the LMNA heterozygous c.1968+2T>C mutation, was referred to our center at the age of five years. She was diagnosed with the disease when she was 10 months old, presenting with a typical HGPS clinical phenotype, including frontal bossing, prominent veins on her scalp and forehead, sparse hair, micrognathism with delayed dentition, growth retardation, subcutaneous lipoatrophy, dry skin with pigmentary changes on the neck and trunk, acroosteolyses with the onychodystrophy of hands and feet; laboratory findings have evidenced recurrent thrombocytosis (480–535 k/μL; normal values: 140–450 k/μL), elevated transaminases, glucose, calcium, and phosphorus, as already observed in classical HGPS patients [17]

Summary

Introduction

Progeroid syndromes (PS) are a group of very rare genetic disorders associated with clinical features that mimic physiological aging. Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670) is the most prevalent and widely studied syndrome among PS. Estimates indicate that the prevalence of HGPS is approximately one in 4 million children [1]. HGPS is characterized by premature and accelerated aging with rapid growth retardation, thin skin, loss of subcutaneous fat, alopecia, osteoporosis, and cardiovascular disease

Methods

Results

Conclusion