Neuropharmacology

Biography

Biography: Malka Cohen-Armon

Abstract

Unexpectedly, a post-translational modification of DNA-binding proteins initiating the cell response to single-strand DNA damage is also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk2 synergism, which can underlie this phenomenon. This mechanism is activated by a high frequency electrical stimulation inducing Erk phosphorylation. PARP1 binding to phosphorylated Erk2 via docking sites in the catalytic domain of PARP1, caused PARP1 activation that mediated the recruitment of PARP1-bound phosphorylated Erk2 to promoters of Immediate Early Genes (IEG) implicated in synaptic plasticity and long-term potentiation (LTP). PARP1 inhibition, silencing, or genetic deletion abrogated both stimulation-induced IEG expression and LTP induction. They were similarly abrogated by a predominate binding of PARP1 to single-strand DNA breaks that occluded the binding sites of Erk in PARP1. These findings outline a PARP1-dependent mechanism governing Erk-induced IEG expression implicated in synaptic plasticity. It may underlie the pivotal role of polyADP-ribosylation in long-term memory acquisition, and the deterioration in learning abilities most frequently experienced in senescence.