%0 Journal Article
%T Decreased Phosphorylation and Increased Methionine Oxidation of ¦Á-Synuclein in the Methionine Sulfoxide Reductase A Knockout Mouse
%A Derek B. Oien
%A Gonzalo A. Carrasco
%A Jackob Moskovitz
%J Journal of Amino Acids
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/721094
%X Previously, we have showed that overexpression of methionine-oxidized ¦Á-synuclein in methionine sulfoxide reductase A (MsrA) null mutant yeast cells inhibits ¦Á-synuclein phosphorylation and increases protein fibrillation. The current studies show that ablation of mouse MsrA gene caused enhanced methionine oxidation of ¦Á-synuclein while reducing its own phophorylation levels, especially in the hydrophobic cell-extracted fraction. These data provide supportive evidence that a compromised MsrA function in mammalian brain may cause enhanced pathologies associated with altered ¦Á-synuclein oxidation and phosphorylation levels. 1. Introduction Parkinson¡¯s disease (PD) is characterized by the formation of neuronal inclusion bodies that are denoted as Lewy bodies [1]. These bodies consist mainly of ¦Á-synuclein fibrils [2]. The ¦Á-synuclein protein is a presynaptic and its function and involvement in the development of PD is yet to be clearly determined. When ¦Á-synuclein is abnormally expressed or modified, various studies indicate it may cause alterations in mitochondrial and proteasomal function, protein aggregation, and accumulation of reactive oxygen species (ROS) [3¨C6]. Increased ROS and cellular ¦Á-synuclein levels promote its aggregation [7, 8] and can cause posttranslational modifications to the methionine (Met) residues of ¦Á-synuclein leading to the formation of methionine sulfoxide (MetO)¡ªcontaining ¦Á-synuclein (MetO-¦Á-synuclein). MetO modifications can be present in two forms of enantiomers: Met-S-O and Met-R-O that can be readily reduced by the methionine sulfoxide reductase (Msr) system. Msr type A (MsrA) reduces Met-S-O and Msr type B (MsrB) reduces Met-R-O [9, 10]. MsrA is thought to be the major Msr because it is a positive regulator of MsrB expression levels [11, 12]. Absence of MsrA can cause a hypervulnerability to conditions of oxidative stress [13¨C17] and shortened lifespan [16, 18]. One possible explanation is that the cellular regulation of aging neurons (e.g., in PD) is altered and consequently causes the accumulation of misfolded proteins (e.g., ¦Á-synuclein) [19]. The functional role of phosphorylation to ¦Á-synuclein is not completely and clearly understood. Previous work has determined that msrA knockout yeast strain expressing either of the three ¦Á-synuclein types (normal type ¦Á-synuclein (Syn) and Syn mutant types: SynA30P, SynA53T) showed significantly lower levels of phosphorylation relative to ¦Á-synuclein expressed in wild-type cells [22]. These data suggest that increased levels of MetO moiety in ¦Á-synuclein could inhibit its
%U http://www.hindawi.com/journals/jaa/2011/721094/