Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Abstract

Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and α-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant α-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetyl-cysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant α-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD. Keywords aggresome; dopamine; glutathione; heat shock protein; methionine sulfoxide reductase; neurodegeneration; oxidative stress; Parkinson's disease; proteasome; protofibril; rotenone; synuclein Parkinson's disease (PD) is a neurologic disorder that involves a selective loss of dopaminergic neurons from the substantia nigra [1,2]. The postmortem brains of PD patients are characterized by reduced activity of mitochondrial complex I, an enzyme of the mitochondrial electron transport chain [3,4]. In turn, this defect may cause a 'leakage' of electrons from mitochondria, leading to the accumulation of reactive oxygen species (ROS) that damage *Corresponding author. Address: Jean-Christophe Rochet, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 410A, West Lafayette, Indiana, 47907-209147907- . Fax: 765-494-1414. E-mail: rochet@pharmacy.purdue.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2009 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript proteins, lipids, and nucleic acids [3,5]. The brains of PD patients also show evidence of impaired proteasomal function [6], a defect that results in increased oxidative stress and decreased elimination...

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

“…It has even been hypothesized that α-synuclein itself, through its reversible methionine oxidation and reduction driven by methionine sulfoxide reductase (Msr), may serve as a cellular antioxidant [148] by transferring oxygenbased radicals that are generated in modest amounts at cell membranes (i.e., lipid peroxidation products) to more stable and easily contained carbon-centered radicals [149]. This notion is consistent with findings that increased expression of MsrA in Drosophila prevents α-synuclein-dependent locomotor and circadian rhythm deficits [150] and MsrA protects against mutant α-synuclein-induced toxicity in cultured cells [151]. A thorough review of the oxidative and nitrative changes that occur in α-synuclein and their effects on aggregation and toxicity is the subject of a recent review [147].…”

Methionine Sulfoxide Reductase A Negatively Controls Microglia-Mediated Neuroinflammation via Inhibiting ROS/MAPKs/NF-κB Signaling Pathways Through a Catalytic Antioxidant Function

“…Thus, MsrA may act as a new number in the vitagenes network for its cytoprotection and inducible expression during stressful conditions. Previous studies have revealed that enhancing MsrA function may be beneficial in Parkinson's disease (PD) and Alzheimer's disease (AD) via scavenging ROS and repairing methionine sulfoxide (35,43,64). Taken together, our results suggest that MsrA negatively controls microglia-mediated neuroinflammation, and pharmacological enhancement of MsrA function may serve as a reasonable therapeutic strategy aimed at reducing neurodegeneration in the clinic.…”

Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson’s disease models

“…None of the antioxidants protected against the cellular toxicity of -syn in yeast (supplementary material Figs S6-S8). Similarly, these antioxidants did not protect against the toxicity of -syn in the nematode or rat midbrain neuronal culture models (Liu et al, 2008b) (supplementary material Figs S9 and S10). Thus, rescue of toxicity by these compounds is not due to simple antioxidant activity.…”