The aim of this study is to compare the proteome of Prnp-/- (Zürich I) gene-ablated mouse brains with wild-type mouse brains. Fluorescence two-dimensional-difference gel electrophoresis (DIGE) and isotope-coded protein labeling (ICPL) were applied for brain homogenates. Similar quantitative protein profiles (<or=1.5-fold change, P<0.05) were obtained by quantitative two-dimensional-DIGE analysis of whole brain homogenates of two developmental stages (days 1 and 67). Complementary ICPL-liquid chromatography-mass spectrometry experiments (n=5) of whole brain homogenates and synaptosomes were performed. The abundance ratios of all proteins quantified did not exceed the statistical spread determined (<2-fold). Therefore, both of the two-dimensional-DIGE and ICPL analyses demonstrated a highly conserved quantitative protein profile in brain homogenates of Prnp-/- and Prnp+/+ mice.