Methionine Sulfoxide Reductase A and a Dietary SupplementS-Methyl-L-Cysteine Prevent Parkinson's-Like Symptoms

Abstract

Parkinson's disease (PD), a common neurodegenerative disease, is caused by loss of dopaminergic neurons in the substantia nigra. Although the underlying cause of the neuronal loss is unknown, oxidative stress is thought to play a major role in the pathogenesis of PD. The amino acid methionine is readily oxidized to methionine sulfoxide, and its reduction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs). The reversible oxidation-reduction cycle of methionine involving MSRs has been postulated to act as a catalytic antioxidant system protecting cells from oxidative damage. Here, we show that one member of the MSR family, MSRA, inhibits development of the locomotor and circadian rhythm defects caused by ectopic expression of human ␣-synuclein in the Drosophila nervous system. Furthermore, we demonstrate that one way to enhance the MSRA antioxidant system is dietary supplementation with S-methyl-L-cysteine (SMLC), found abundantly in garlic, cabbage, and turnips. SMLC, a substrate in the catalytic antioxidant system mediated by MSRA, prevents the ␣-synuclein-induced abnormalities. Therefore, interventions focusing on the enzymatic reduction of oxidized methionine catalyzed by MSRA represent a new prevention and therapeutic approach for PD and potentially for other neurodegenerative diseases involving oxidative stress.

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

“…Moreover, the methionine analog S-methyl-L-cysteine was recently found to delay the onset of motor deficits in α-synuclein transgenic flies, possibly by activating an MsrA-driven redox cycle [28]. These observations imply that the MsrA repair function is not the only activity involved in mitigating α-synuclein-induced cell death -rather, other functions such as MsrA-mediated ROS scavenging may also contribute to neuroprotection.…”

“…Other groups have reported that MsrA is neuroprotective in vitro [21,50] and in vivo [25], and data from one study indicate that MsrA levels are decreased in the brains of Alzheimer's disease patients compared to age-matched controls [51]. A very recent study revealed that MsrA alleviates motor dysfunction and neurodegeneration in transgenic flies over-expressing α-synuclein [28]. Our data are the first to show in a mammalian system that MsrA suppresses dopaminergic cell death and protein aggregation elicited by toxic phenomena involved in PD.…”

“…MsrA activity decreases with age in rats [27], and this decrease coupled with the resulting age-related increase in oxidative stress may explain in part why the incidence of PD increases with age [1,2]. A very recent study revealed that MsrA expression slows age-related motor defects and neurodegeneration in transgenic Drosophila over-expressing α-synuclein [28].Although evidence suggests that MsrA has a neuroprotective function associated with longevity [25], it is uncertain whether the enzyme specifically inhibits dopaminergic cell death in PD. Because oxidative stress is critically involved in dopaminergic neurodegeneration, we hypothesized that MsrA plays a major role in dopamine neuron survival.…”

“…MsrA activity decreases with age in rats [27], and this decrease coupled with the resulting age-related increase in oxidative stress may explain in part why the incidence of PD increases with age [1,2]. A very recent study revealed that MsrA expression slows age-related motor defects and neurodegeneration in transgenic Drosophila over-expressing α-synuclein [28].…”

Oxidative and nitrative protein modifications in Parkinson's disease

“…The reverse reduction reaction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs). In a α-synuclein Drosophila model, overexpression of MSRA was found to prevent the decreased locomotor activity and shortened lifespan caused by elevated α-synuclein [53].…”