J B Strosznajder
Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland
Title: PARP-1 inhibition modulates gene expression of mitochondria sirtuins and APP secretases: The role of PARP and sirts interaction in amyloid beta toxicity
Biography
Biography: J B Strosznajder
Abstract
Poly(ADP-ribose) polymerase-1(PARP-1) is responsible for 90% of protein poly(ADP-ribosylation in the brain and is a key cellular NAD+ consumer involved in DNA repair. However, its over activation leads to cells death. Intracellular NAD+ level also regulates the activity of type III the histone deacetylases sirtuins (Sirts). The interplay between PARPs and sirts is crucial in genomic stability and energy metabolism. Our recent study is focused on the effect of amyloid beta on signaling pathways and the role of PARP-1 in regulation of gene expression for enzymes involved in processing of AB precursor protein (APP) and mitochondrial sirts. PC12 cells transfected with human genes for wild type APP and bearing double Swedish mutation (APPwt and APPsw) were used in this study. Additionally the effects of extracellular AB on PC12 cells were examined. Our data showed that AB 42 decreases gene expression of secretase alpha (ADAM10), the main enzyme in non amyloidogenic metabolism of APP, and enhances expression for secretase beta (BACE-1) and subunits of secretase gamma which are responsible for the liberation of AB. Endogenous AB peptides liberated in APPwt and APPsw cells activate gene expression for BACE1 and secretase gamma subunits. AB also activates mitochondria sirt(s) and DNA bound PARPs expression. Pharmacological inhibition of PARP-1 leads to down regulation of gene expression for BACE1 and activates of mitochondrial sirts transcription. It seems that specific activators of Sirt1 and Sirt3 and also PARP-1 inhibitors will be promising for cytoprotection against AB and other amyloidogenic proteins in neurodegenerative diseases.