Prelamin A degradation pathways and progeria

The nuclear lamina plays a key role in cellular senescence. Lamin A precursors have been implicated in the normal ageing process, while mutations in lamin A/C cause progeroid diseases, such as Mandibuloacral dysplasia and Hutchinson-Gilford progeria, or developmental diseases such as Restrictive Dermopathy. Accumulation of farnesylated prelamin A, one of the intermediates in the maturation pathway of lamin A, is toxic to cells, leading to chromatin damage and cellular senescence. Here, we show that non-farnesylated prelamin A is more susceptible to degradation, while its partially processed farnesylated form is stable under basal conditions. However, treatment with rapamycin, an antibiotic previously shown to induce autophagy and extend longevity in animal models, efficiently and selectively triggers lysosomal degradation of farnesylated prelamin A. In Restrictive Dermopathy cells, where prelamin A maturation is abolished, rapamycin-triggered prelamin A degradation rescues the chromatin phenotype. In Mandibuloacral dysplasia fibroblasts, where prelamin A is accumulated to less toxic levels due to spontaneous activation of the lysosomal degradation pathway, drug treatment improves chromatin organization. Thus, rapamycin, can be considered a potential therapeutic tool in progeroid laminopathies and ageing diseases.