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A new mechanism for protection of dopaminergic neurons mediated by astrocytes.

Segura-Aguilar J - Neural Regen Res (2015)

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.

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For a long time, the question about the mechanism involved in the degenerative process of the nigrostriatal system in Parkinson's disease (PD), resulting in the loss of dopaminergic neurons containing neuromelanin, has remained open... The discovery of genes associated with familial forms of PD, such as α-synuclein (SNCA), parkin, DJ-1, PINK-1, LRRK-2, ATP13A2, PINK-1 and others resulted in important input into the basic research in this field with the aim of understanding the role of these proteins in sporadic PD... In the scientific community, there is a general agreement that the loss of dopaminergic neurons containing neuromelanin in the nigrostriatal system involves mitochondria dysfunction, protein degradation dysfunction, and SNCA aggregation in neurotoxic oligomers, oxidative stress, neuroinflammation and endoplasmic reticulum stress (Segura-Aguilar et al., 2014)... It seems to be plausible that the neurotoxin involved in the degenerative process of the dopaminergic nigrostriatal system must be of endogenous origin, since the progression of the neurodegenerative process in PD is very slow and takes years for the development of motor symptoms, when up to 60–70% of dopaminergic neurons containing neuromelanin are lost... The possibility that o-quinones derived from dopamine oxidation are responsible for the loss of dopaminergic neurons containing neuromelanin in PD is supported by the fact that these neurons require dopamine oxidation to o-quinones to generate neuromelanin... Interestingly, o-quinones generated during dopamine oxidation have been reported to induce mitochondria dysfunction, SNCA aggregation in neurotoxic oligomers, protein degradation dysfunction of both proteasomal and lysosomal systems, oxidative and endoplasmic reticulum stress (Segura-Aguilar et al., 2014)... Dopamine oxidation to o-quinones seems to be a natural process resulting in the formation of neuromelanin, since this pigment is found in dopaminergic neurons localized in the substantia nigra of the brain of healthy individuals... However, under certain conditions, the o-quinones formed during dopamine oxidation participate in neurotoxic reactions, such as the formation of adduct with proteins and one-electron reduction, to generate an o-semiquinone radical... Dopamine oxidation to o-quinones has been found to inactivate chaperone-mediated autophagy... Dopamine-o-quinone has been found (i) to inactivate the proteasome system by forming adducts with parkin; (ii) to inactivate mitochondrial complexes I, III and V, which results in mitochondrial dysfunction; and (iii) to inactivate other proteins such as dopamine transporter, tyrosine hydroxylase, UCHL-1, and DJ-1... The constitutive expression of DT-diaphorase prevents o-quinones that formed during dopamine oxidation from participating in neurotoxic reactions, such as the formation of adducts with proteins and one-electron reduction to o-semiquinone radicals... DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome and this is expressed both in neurons and astrocytres... Therefore, astrocytes seem to play a very important role in the prevention of neurodegeneration of dopaminergic neurons in PD.

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DT-diaphorase protects against aminochrome neurotoxicity.DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome, preventing the neurotoxic actions of aminochrome, such as (i) formation of adducts with α-synuclein (SNCA); (ii) formation of adducts with complex I of mitochondria and subsequent mitochondrial dysfunction; (iii) one-electron reduction to leukoaminochrome o-semiquinone radical and subsequent oxidative stress; (iv) inhibition of degradation of proteins as a consequence of proteasome inactivation; (v) inhibition of degradation of proteins and organelles with autophagy; and (vi) formation of adducts with α- and β-tubulin and subsequent aggregation. Leukoaminochrome can tautomerize to 5,6-dihydroxyindole, which can oxidize to 5,6-indolequinone which is the precursor of neuromelanin.
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Figure 3: DT-diaphorase protects against aminochrome neurotoxicity.DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome, preventing the neurotoxic actions of aminochrome, such as (i) formation of adducts with α-synuclein (SNCA); (ii) formation of adducts with complex I of mitochondria and subsequent mitochondrial dysfunction; (iii) one-electron reduction to leukoaminochrome o-semiquinone radical and subsequent oxidative stress; (iv) inhibition of degradation of proteins as a consequence of proteasome inactivation; (v) inhibition of degradation of proteins and organelles with autophagy; and (vi) formation of adducts with α- and β-tubulin and subsequent aggregation. Leukoaminochrome can tautomerize to 5,6-dihydroxyindole, which can oxidize to 5,6-indolequinone which is the precursor of neuromelanin.

Mentions: Dopaminergic neurons are the most vulnerable cells exposed to neurotoxic o-quinones generated during dopamine oxidation. Dopaminergic neurons have both dopamine synthesis from tyrosine and dopamine reuptake mediated by dopamine transporters from the synaptic cleft. Dopamine is stored in monoaminergic vesicles to be used for neurotransmission, and dopamine excess is degraded by monoamino oxidase, which catalyzes the oxidative deamination of the dopamine amino group. However, under certain unknown conditions, free dopamine in the cytosol is oxidized to o-quinones that normally result in the formation of neuromelanin. The presence of neuromelanin in substantia nigra in the brain of healthy individuals support the idea that dopamine oxidation occurs in vivo despite the presence of vesicular monoamine transporter-2 and monoamine oxidase. The constitutive expression of DT-diaphorase prevents o-quinones that formed during dopamine oxidation from participating in neurotoxic reactions, such as the formation of adducts with proteins and one-electron reduction to o-semiquinone radicals. DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome and this is expressed both in neurons and astrocytres. DT-diaphorase protects dopaminergic neurons from aminochrome-induced (i) cell death; (ii) formation of neurotoxic α-synuclein oligomers (Muñoz et al., 2015); (iii) mitochondria dysfunction; (iv) inhibition of the proteasomal system; (v) inhibition of autophagy (Muñoz et al., 2012); (vi) inhibition of α- and β-tubulin aggregation and cell shrinkage; and (vii) inhibition of oxidative stress (Figure 3). GSTM2 is not expressed in dopaminergic neurons, and therefore, the importance of this new mechanism of dopaminergic neuron protection, mediated by the internalization of GSTM2 secreted from astrocytes, is to reinforce the neuroprotection provided by DT-diaphorase against aminochrome generated during dopamine oxidation. GSTM2 catalyzes the conjugation of both aminochrome and dopamine o-quinone, which provides a wider protection in dopaminergic neurons. Therefore, astrocytes seem to play a very important role in the prevention of neurodegeneration of dopaminergic neurons in PD.


A new mechanism for protection of dopaminergic neurons mediated by astrocytes.

Segura-Aguilar J - Neural Regen Res (2015)

DT-diaphorase protects against aminochrome neurotoxicity.DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome, preventing the neurotoxic actions of aminochrome, such as (i) formation of adducts with α-synuclein (SNCA); (ii) formation of adducts with complex I of mitochondria and subsequent mitochondrial dysfunction; (iii) one-electron reduction to leukoaminochrome o-semiquinone radical and subsequent oxidative stress; (iv) inhibition of degradation of proteins as a consequence of proteasome inactivation; (v) inhibition of degradation of proteins and organelles with autophagy; and (vi) formation of adducts with α- and β-tubulin and subsequent aggregation. Leukoaminochrome can tautomerize to 5,6-dihydroxyindole, which can oxidize to 5,6-indolequinone which is the precursor of neuromelanin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590230&req=5

Figure 3: DT-diaphorase protects against aminochrome neurotoxicity.DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome, preventing the neurotoxic actions of aminochrome, such as (i) formation of adducts with α-synuclein (SNCA); (ii) formation of adducts with complex I of mitochondria and subsequent mitochondrial dysfunction; (iii) one-electron reduction to leukoaminochrome o-semiquinone radical and subsequent oxidative stress; (iv) inhibition of degradation of proteins as a consequence of proteasome inactivation; (v) inhibition of degradation of proteins and organelles with autophagy; and (vi) formation of adducts with α- and β-tubulin and subsequent aggregation. Leukoaminochrome can tautomerize to 5,6-dihydroxyindole, which can oxidize to 5,6-indolequinone which is the precursor of neuromelanin.
Mentions: Dopaminergic neurons are the most vulnerable cells exposed to neurotoxic o-quinones generated during dopamine oxidation. Dopaminergic neurons have both dopamine synthesis from tyrosine and dopamine reuptake mediated by dopamine transporters from the synaptic cleft. Dopamine is stored in monoaminergic vesicles to be used for neurotransmission, and dopamine excess is degraded by monoamino oxidase, which catalyzes the oxidative deamination of the dopamine amino group. However, under certain unknown conditions, free dopamine in the cytosol is oxidized to o-quinones that normally result in the formation of neuromelanin. The presence of neuromelanin in substantia nigra in the brain of healthy individuals support the idea that dopamine oxidation occurs in vivo despite the presence of vesicular monoamine transporter-2 and monoamine oxidase. The constitutive expression of DT-diaphorase prevents o-quinones that formed during dopamine oxidation from participating in neurotoxic reactions, such as the formation of adducts with proteins and one-electron reduction to o-semiquinone radicals. DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome and this is expressed both in neurons and astrocytres. DT-diaphorase protects dopaminergic neurons from aminochrome-induced (i) cell death; (ii) formation of neurotoxic α-synuclein oligomers (Muñoz et al., 2015); (iii) mitochondria dysfunction; (iv) inhibition of the proteasomal system; (v) inhibition of autophagy (Muñoz et al., 2012); (vi) inhibition of α- and β-tubulin aggregation and cell shrinkage; and (vii) inhibition of oxidative stress (Figure 3). GSTM2 is not expressed in dopaminergic neurons, and therefore, the importance of this new mechanism of dopaminergic neuron protection, mediated by the internalization of GSTM2 secreted from astrocytes, is to reinforce the neuroprotection provided by DT-diaphorase against aminochrome generated during dopamine oxidation. GSTM2 catalyzes the conjugation of both aminochrome and dopamine o-quinone, which provides a wider protection in dopaminergic neurons. Therefore, astrocytes seem to play a very important role in the prevention of neurodegeneration of dopaminergic neurons in PD.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

For a long time, the question about the mechanism involved in the degenerative process of the nigrostriatal system in Parkinson's disease (PD), resulting in the loss of dopaminergic neurons containing neuromelanin, has remained open... The discovery of genes associated with familial forms of PD, such as α-synuclein (SNCA), parkin, DJ-1, PINK-1, LRRK-2, ATP13A2, PINK-1 and others resulted in important input into the basic research in this field with the aim of understanding the role of these proteins in sporadic PD... In the scientific community, there is a general agreement that the loss of dopaminergic neurons containing neuromelanin in the nigrostriatal system involves mitochondria dysfunction, protein degradation dysfunction, and SNCA aggregation in neurotoxic oligomers, oxidative stress, neuroinflammation and endoplasmic reticulum stress (Segura-Aguilar et al., 2014)... It seems to be plausible that the neurotoxin involved in the degenerative process of the dopaminergic nigrostriatal system must be of endogenous origin, since the progression of the neurodegenerative process in PD is very slow and takes years for the development of motor symptoms, when up to 60–70% of dopaminergic neurons containing neuromelanin are lost... The possibility that o-quinones derived from dopamine oxidation are responsible for the loss of dopaminergic neurons containing neuromelanin in PD is supported by the fact that these neurons require dopamine oxidation to o-quinones to generate neuromelanin... Interestingly, o-quinones generated during dopamine oxidation have been reported to induce mitochondria dysfunction, SNCA aggregation in neurotoxic oligomers, protein degradation dysfunction of both proteasomal and lysosomal systems, oxidative and endoplasmic reticulum stress (Segura-Aguilar et al., 2014)... Dopamine oxidation to o-quinones seems to be a natural process resulting in the formation of neuromelanin, since this pigment is found in dopaminergic neurons localized in the substantia nigra of the brain of healthy individuals... However, under certain conditions, the o-quinones formed during dopamine oxidation participate in neurotoxic reactions, such as the formation of adduct with proteins and one-electron reduction, to generate an o-semiquinone radical... Dopamine oxidation to o-quinones has been found to inactivate chaperone-mediated autophagy... Dopamine-o-quinone has been found (i) to inactivate the proteasome system by forming adducts with parkin; (ii) to inactivate mitochondrial complexes I, III and V, which results in mitochondrial dysfunction; and (iii) to inactivate other proteins such as dopamine transporter, tyrosine hydroxylase, UCHL-1, and DJ-1... The constitutive expression of DT-diaphorase prevents o-quinones that formed during dopamine oxidation from participating in neurotoxic reactions, such as the formation of adducts with proteins and one-electron reduction to o-semiquinone radicals... DT-diaphorase catalyzes the two-electron reduction of aminochrome to leukoaminochrome and this is expressed both in neurons and astrocytres... Therefore, astrocytes seem to play a very important role in the prevention of neurodegeneration of dopaminergic neurons in PD.

No MeSH data available.