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Proteome analysis reveals roles of L-DOPA in response to oxidative stress in neurons.

Jami MS, Pal R, Hoedt E, Neubert TA, Larsen JP, Møller SG - BMC Neurosci (2014)

Bottom Line: We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways.Oxidative stress changes neuronal metabolic routes and affects cytoskeletal integrity.Further, L-DOPA appears to reverse some H2O2-mediated effects evident at both the proteome and cellular level.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St John's University, New York, NY, USA. mollers@stjohns.edu.

ABSTRACT

Background: Parkinson's disease (PD) is the second most common neurodegenerative movement disorder, caused by preferential dopaminergic neuronal cell death in the substantia nigra, a process also influenced by oxidative stress. L-3,4-dihydroxyphenylalanine (L-DOPA) represents the main treatment route for motor symptoms associated with PD however, its exact mode of action remains unclear. A spectrum of conflicting data suggests that L-DOPA may damage dopaminergic neurons due to oxidative stress whilst other data suggest that L-DOPA itself may induce low levels of oxidative stress, which in turn stimulates endogenous antioxidant mechanisms and neuroprotection.

Results: In this study we performed a two-dimensional gel electrophoresis (2DE)-based proteomic study to gain further insight into the mechanism by which L-DOPA can influence the toxic effects of H2O2 in neuronal cells. We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways. Our study underlines the complex nature of L-DOPA in PD and sheds light on the interplay between oxidative stress and L-DOPA.

Conclusions: Oxidative stress changes neuronal metabolic routes and affects cytoskeletal integrity. Further, L-DOPA appears to reverse some H2O2-mediated effects evident at both the proteome and cellular level.

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Biosynthesis of catecholamines. The conversion of L-DOPA to norepinephrine through dopamine requires molecular oxygen.
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Fig6: Biosynthesis of catecholamines. The conversion of L-DOPA to norepinephrine through dopamine requires molecular oxygen.

Mentions: In addition to its effects on the cytoskeleton and mitochondria, L-DOPA seems to participate in a cell survival mechanism triggered by oxygen deprivation through induction of the hypoxia up-regulated protein 1 (ORP150, spot 17), a chaperone involved in protein folding [48]. We observed detectable levels of this protein only in the presence of L-DOPA regardless of the oxidative stress conditions (Table 2) suggesting that L-DOPA may aid hypoxia condition in cells. It has been shown in rat astrocytes that ORP150 is induced by hypoxia within 24 hours, augmented further during early re-oxygenation, and thereafter decreasing to baseline levels by 24 hours in normoxia [49]. Furthermore, the hypoxia-mediated induction of ORP150 appears specific as stress conditions such as heat shock, H2O2, cobalt chloride, 2-deoxyglucose, or tunicamycin does not affect ORP150 levels [49]. Interestingly, exposure to dopamine has similar ORP induction effects as hypoxia in PC12 cells [50]. In the catecholamine synthesis pathway dopamine is the first catecholamine synthesized from L-DOPA where norepinephrine and epinephrine are formed by further metabolic dopamine modifications (Figure 6). The conversion of dopamine to norepinephrine requires oxygen, thus the higher level of oxygen consumption due to L-DOPA exposure may cause cellular hypoxia and therefore induction of ORP150 with its concomitant cytoprotective effects.Figure 6


Proteome analysis reveals roles of L-DOPA in response to oxidative stress in neurons.

Jami MS, Pal R, Hoedt E, Neubert TA, Larsen JP, Møller SG - BMC Neurosci (2014)

Biosynthesis of catecholamines. The conversion of L-DOPA to norepinephrine through dopamine requires molecular oxygen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4125692&req=5

Fig6: Biosynthesis of catecholamines. The conversion of L-DOPA to norepinephrine through dopamine requires molecular oxygen.
Mentions: In addition to its effects on the cytoskeleton and mitochondria, L-DOPA seems to participate in a cell survival mechanism triggered by oxygen deprivation through induction of the hypoxia up-regulated protein 1 (ORP150, spot 17), a chaperone involved in protein folding [48]. We observed detectable levels of this protein only in the presence of L-DOPA regardless of the oxidative stress conditions (Table 2) suggesting that L-DOPA may aid hypoxia condition in cells. It has been shown in rat astrocytes that ORP150 is induced by hypoxia within 24 hours, augmented further during early re-oxygenation, and thereafter decreasing to baseline levels by 24 hours in normoxia [49]. Furthermore, the hypoxia-mediated induction of ORP150 appears specific as stress conditions such as heat shock, H2O2, cobalt chloride, 2-deoxyglucose, or tunicamycin does not affect ORP150 levels [49]. Interestingly, exposure to dopamine has similar ORP induction effects as hypoxia in PC12 cells [50]. In the catecholamine synthesis pathway dopamine is the first catecholamine synthesized from L-DOPA where norepinephrine and epinephrine are formed by further metabolic dopamine modifications (Figure 6). The conversion of dopamine to norepinephrine requires oxygen, thus the higher level of oxygen consumption due to L-DOPA exposure may cause cellular hypoxia and therefore induction of ORP150 with its concomitant cytoprotective effects.Figure 6

Bottom Line: We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways.Oxidative stress changes neuronal metabolic routes and affects cytoskeletal integrity.Further, L-DOPA appears to reverse some H2O2-mediated effects evident at both the proteome and cellular level.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St John's University, New York, NY, USA. mollers@stjohns.edu.

ABSTRACT

Background: Parkinson's disease (PD) is the second most common neurodegenerative movement disorder, caused by preferential dopaminergic neuronal cell death in the substantia nigra, a process also influenced by oxidative stress. L-3,4-dihydroxyphenylalanine (L-DOPA) represents the main treatment route for motor symptoms associated with PD however, its exact mode of action remains unclear. A spectrum of conflicting data suggests that L-DOPA may damage dopaminergic neurons due to oxidative stress whilst other data suggest that L-DOPA itself may induce low levels of oxidative stress, which in turn stimulates endogenous antioxidant mechanisms and neuroprotection.

Results: In this study we performed a two-dimensional gel electrophoresis (2DE)-based proteomic study to gain further insight into the mechanism by which L-DOPA can influence the toxic effects of H2O2 in neuronal cells. We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways. Our study underlines the complex nature of L-DOPA in PD and sheds light on the interplay between oxidative stress and L-DOPA.

Conclusions: Oxidative stress changes neuronal metabolic routes and affects cytoskeletal integrity. Further, L-DOPA appears to reverse some H2O2-mediated effects evident at both the proteome and cellular level.

Show MeSH
Related in: MedlinePlus