A new target in progeria

A recent study suggests that targeting the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT) might have therapeutic benefit in a mouse model of a premature aging disease (Science http://dx.doi.org/10.1126/science.1238880).

A number of progeroid disorders are caused by the accumulation of an aberrant form of prelamin A at the nuclear envelope, leading to misshapen nuclei. Prelamin A is post translationally modified at its C terminal by farnesylation and subsequent ICMT-mediated methylation. Mohamed X. Ibrahim et al. investigated the role of ICMT in the disease phenotype of a mouse model of progeria caused by knockout of the gene Zmpste24. Taking advantage of a hypomorphic allele of Icmt (Icmt^hm), they found that Zmpste24^−/−;Icmt^hm/hm mice showed improvement in several symptoms associated with progeria compared with Zmpste24^−/− mice that had normal expression of Icmt.

In fibroblasts from the Zmpste24^−/−;Icmt^hm/hm mice, prelamin A was relocalized away from the nuclear rim, although the nuclei were still misshapen. In contrast to Zmpste24^−/− fibroblasts, which proliferate slowly and enter senescence prematurely, Zmpste24^−/−;Icmt^hm/hm fibroblasts showed wild-type rates of proliferation. Mechanistically, these effects seem to be mediated by upregulation of AKT1–mTOR signaling in conditions of Icmt deficiency. The authors then extended these findings to the human situation by inhibiting ICMT in cells from people with Hutchinson-Gilford progeria syndrome (HGPS) using either shRNAs or a pharmacological inhibitor, showing that, as in the mouse cells, ICMT inhibition resulted in increased proliferation and delayed senescence.