Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis

Protein L-isoaspartyl methyltransferase (Pimt) is a highly conserved enzyme utilising S-adenosylmethionine (AdoMet) to methylate aspartate residues of proteins damaged by age-related isomerisation and deamidation. We have bee n particularly interested in this enzyme since addition of the compound CGP 3466 to primary rat astroglia cell cultures resulted in an upregulation of Pimt at the mRNA level, as shown here by semi-quantitative RT-PCR. CGP3466 is a compound related to the anti-Parkinson's drug R-(-)-deprenyl, which ha s been shown to protect from neural apoptosis induced by trophic factor wit hdrawal [Tatton et al., 1994. J. Neurochem, 63, 1572]. The pro-apoptotic ge ne Bar is required in the cascade of events following withdrawal [Deckwerth et al., 1996. Neuron 17, 401]. We therefore investigated whether Pimt over expression was able to affect Bar-induced apoptosis in primary mouse cortic al neurons. Our results show that Pimt is indeed able to protect from Bar-i nduced apoptosis. Furthermore, this activity is not restricted to brain-spe cific cell types, since the same effect is also demonstrated in COS1 cells. In addition, mutational analysis suggests that the protective effect is de pendent on the adenosine methionine-binding motif, which is well conserved in protein methyltransferases, and that a mutation destroying this motif cr ucially affects cytoskeletal structures of the cell. (C) 1999 Elsevier Scie nce B.V. All rights reserved.