Inactivation of the paraoxonase 1 gene affects the expression of mouse brain proteins involved in neurodegeneration

Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Paraoxonase 1 (Pon1) participates in Hcy metabolism and is also linked to AD. The inactivation of the Pon1 gene in mice causes the accumulation of Hcy-thiolactone in the brain and increases the susceptibility to Hcy-thiolactone-induced seizures. To gain insight into the brain-related Pon1 function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to study brain proteomes of Pon1-/- and Pon1+/+ mice fed with a hyperhomocysteinemic high-methionine (Met) or a control diet. We found that: 1) proteins involved in brain-specific function (Nrgn), antioxidant defenses (Sod1, DJ-1), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Pon1-null mice; 2) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1), antioxidant defenses (Prdx2, DJ-1), energy metabolism (Ak1), cell cycle (GDI1, Ran), cytoskeleton assembly (Tbcb), and unknown function (Hdhd2) showed differential expression in brains of Pon1-null fed with a hyperhomocysteinemic high-Met diet; 3) most proteins regulated by the Pon1-/- genotype were also regulated by the high-Met diet; 4) the proteins differentially expressed in Pon1-null mouse brains play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Pon1 interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that these interactions are modulated by hyperhomocysteinemia and account for the involvement of Hcy and Pon1 in AD.