Figure 9.

A. Hypothetical model for the toxicity of progerin and elevated levels of wild-type lamin A is shown. Prelamin A processing time in normal cells has been set arbitrarily as 1. Abnormal processes/steps are shown in red. i): maturation pathway of prelamin A in normal cells; ii): progeria cells display an exceptionally high processing time as the farnesyl group on mutant lamin A cannot be cleaved by ZMPSTE24. This conditions lead to cellular aging that can be partially reversed by decreasing the number of farnesylated molecules in the cell by treatment with FTIs iii): Elevated levels of wild-type lamin A expression do not change the prelamin A processing time as the synthesis of mature lamin is not affected, but increase the overall number of prelamin A intermediates at a given time. This conditions lead to cellular aging. iv): over-expression of ZMPSTE24 reduces the prelamin A processing time and rescues the cellular aging phenotype in cells with elevated levels of wild-type lamin A expression. B. Lamin A metabolism is precisely poised such that small increases in the steady-state levels of one or more prelamin A intermediates caused by increased lamin A expression or decreased ZMPSTE24 activity can propel the cell into a cellular aging phenotype.