Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions.

Oxidative stress and aggregation of the presynaptic protein alpha-synuclein (alpha-Syn) are implied in the pathogenesis of Parkinson's disease and several other neurodegenerative diseases. Various posttranslational modifications, such as oxidation, nitration and truncation, have significant effects on the kinetics of alpha-Syn fibrillation in vitro. alpha-Syn is a typical natively unfolded protein, which possesses some residual structure.

Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter.

Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice.

Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation.

Several observations have implicated oxidative stress and aggregation of the presynaptic protein alpha-synuclein in the pathogenesis of Parkinson disease. alpha-Synuclein has been shown to have affinity for unsaturated fatty acids and membranes enriched in polyunsaturated fatty acids, which are especially sensitive to oxidation under conditions of oxidative stress. One of the most important products of lipid oxidation is 4-hydroxy-2-nonenal (HNE), which has been implicated in the pathogenesis of Parkinson disease.

Comparison of the neurotoxic effects of proteasomal inhibitors in primary mesencephalic cultures.

Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of Parkinson's disease (PD). Because the neurodegenerative process of PD results in a severe loss of dopaminergic cells, previous in vitro studies have investigated the possibility that these neurons may be particularly vulnerable to proteasomal inhibition. Results of this earlier work are difficult to compare, however, since they were obtained using different proteasomal inhibitors at various concentrations and under diverse culture conditions.

Lack of nigrostriatal pathology in a rat model of proteasome inhibition.

Systemic administration of ubiquitin-proteasome system inhibitors to rodents has been reported to induce certain behavioral and neuropathological features of Parkinson's disease. The goal of this study was to replicate these observations by administering a proteasome inhibitor (PSI) to rats using McNaught and colleagues' protocol. No alterations in locomotor activity or striatal dopamine and its metabolites were observed.

Brain accumulation and toxicity of Mn(II) and Mn(III) exposures.

Concern over the neurotoxic effects of chronic moderate exposures to manganese has arisen due to increased awareness of occupational exposures and to the use of methylcyclopentadienyl manganese tricarbonyl, a manganese-containing gasoline antiknock additive. Little data exist on how the oxidation state of manganese exposure affects toxicity. The objective of this study was to better understand how the oxidation state of manganese exposure affects accumulation and subsequent toxicity of manganese.

Redox cycling of the herbicide paraquat in microglial cultures.

Mechanisms involved in paraquat neurotoxicity that selectively target nigrostriatal dopaminergic neurons remain relatively unknown. In this study, we tested the hypotheses that paraquat exposure leads to the production of reactive oxygen species (ROS) through a process of redox cycling and that microglia represent an important site for the initiation of redox cycling reactions. Addition of paraquat to N9 microglial cultures resulted in a dose- and time-dependent release of superoxide radicals.

Alterations in cellular IRP-dependent iron regulation by in vitro manganese exposure in undifferentiated PC12 cells.

Manganese (Mn) may interfere with iron regulation by altering the binding of iron regulatory proteins (IRPs) to their response elements found on the mRNA encoding proteins critical to iron homeostasis. To explore this, the effects of 24-h in vitro manganese exposure (1, 10, 50, and 200 microM Mn) on: (i) total intracellular and labile iron concentrations; (ii) the cellular abundance of transferrin receptor (TfR), H- and L-ferritin, and mitochondrial aconitase proteins; and (iii) IRP binding to a [32P](-) labeled mRNA sequence of L-ferritin were evaluated in undifferentiated PC12 cells. In vitro manganese exposure altered the cellular abundance of TfR, H-/L-ferritin, and m-aconitase, resulting in an increase in labile iron.

Manganese oxidation state and its implications for toxicity.

Manganese (Mn) is ubiquitous in mammalian systems and is essential for proper development and function, though it can also be toxic at elevated exposures. While essential biologic functions of Mn depend on its oxidation state [e.g.