The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells

Maruyama, Wakako; Shamoto-Nagai, Masayo; Akao, Yukihiro; Riederer, Peter; M, Naoi

doi:10.1007/978-3-211-45295-0_20

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…The oxidation potential of neuromelanin is not able to reduce oxygen, but the degradation of the eumelanin surface in the neuromelanin exposes pheomelanin to the surface, which has an oxidation potential that it is able to reduce oxygen (). Neuromelanin has been reported to inhibit 26S proteasome activity ( , ). It is reasonable to think that the dopamine oxidation to aminochrome and the subsequent polymerization to melaninic compound are normal processes due to the presence of DT-diaphorase activity, which prevents the aminochrome conversion to neurotoxic species generated by one-electron reduction.…”

Section: Discussionmentioning

confidence: 99%

“…The oxidation potential of neuromelanin is not able to reduce oxygen, but the degradation of the eumelanin surface in the neuromelanin exposes pheomelanin to the surface, which has an oxidation potential that it is able to reduce oxygen (12). Neuromelanin has been reported to inhibit 26S proteasome activity (42,43). Transmission electron microscopy of RCSN-3 cells treated for 6 h. We can observe the cell's surface with microprojections and microvilli (M with black arrows) not only in control cells incubated with serum and phenol red-free culture medium alone (A) but also in cells treated with 100 µM dopamine (B), 1 µM reserpine (C), 100 µM dicoumarol (D), and 100 µM dopamine and 1 µM reserpine (E).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of VMAT-2 and DT-Diaphorase Induce Cell Death in a Substantia Nigra-Derived Cell LineAn Experimental Cell Model for Dopamine Toxicity Studies

Fuentes¹,

Paris²,

Nassif³

et al. 2007

Chem. Res. Toxicol.

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We have induced intracellular dopamine oxidation to aminochrome in RCSN-3 cells derived from rat substantia nigra by inhibiting VMAT-2 with reserpine to increase free cytosolic dopamine concentration, to study aminochrome-dependent neurotoxicity in the absence of exogenous oxidizing agents such as metals, which may potentiate an aminochrome cytotoxic effect. The expression of VMAT-2 in RCSN-3 cells was determined by reverse transcriptase-polymerase chain reaction and immunocytochemistry. We observed double membrane bodies containing melanin when RCSN-3 cells were incubated with 100 microM dopamine by using transmission electron microscopy. No significant difference in the cell death was observed when the cells were treated 100 microM dopamine and 25 microM reserpine in the absence or presence of 100 microM dicoumarol, an inhibitor of DT-diaphorase. The lack of effect was due to the inhibitory action of 25 microM reserpine on DT-diaphorase (Ki = 24 microM). However, a significant increase in the cell death was observed when DT-diaphorase was inhibited when the cells were incubated with 1 microM reserpine and 100 microM dopamine for 12 h since at this concentration reserpine inhibits VMAT-2 but not DT-diaphorase. Under this condition, we observed (i) the formation of blebbing; (ii) chromatin condensation accompanied by the formation of massive patches in contact with the nuclear membrane; (iii) the smoothness of the cell's surface, that is, lack of surface microprojections; and (iv) mitochondrial damage characterized by disruption of cristae architecture, which remains closely packed; disorganization of the mitochondrial matrix due to separation of the outer membrane from the internal membrane and considerable enlargement of the intermembrane space; and disruption of the external mitochondrial membrane determined by transmission electron microscopy. These results support the proposed neuroprotective role of DT-diaphorase against aminochrome neurotoxicity, and it suggests that RCSN-3 cells incubated with reserpine and dopamine are an excellent and more physiological cellular experimental model to study the role of dopamine oxidation in neurotoxic effects of dopamine.

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Section: Discussionmentioning

confidence: 99%

“…The oxidation potential of neuromelanin is not able to reduce oxygen, but the degradation of the eumelanin surface in the neuromelanin exposes pheomelanin to the surface, which has an oxidation potential that it is able to reduce oxygen (12). Neuromelanin has been reported to inhibit 26S proteasome activity (42,43). Transmission electron microscopy of RCSN-3 cells treated for 6 h. We can observe the cell's surface with microprojections and microvilli (M with black arrows) not only in control cells incubated with serum and phenol red-free culture medium alone (A) but also in cells treated with 100 µM dopamine (B), 1 µM reserpine (C), 100 µM dicoumarol (D), and 100 µM dopamine and 1 µM reserpine (E).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VMAT-2 and DT-Diaphorase Induce Cell Death in a Substantia Nigra-Derived Cell LineAn Experimental Cell Model for Dopamine Toxicity Studies

Fuentes¹,

Paris²,

Nassif³

et al. 2007

Chem. Res. Toxicol.

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“…This hypothesis has been difficult to test empirically, as animal models of Parkinsons disease do not produce NM within dopaminergic substantia nigra neurons. A feature of the parkinsonian brain is the presence of unusually high amounts of extracellular NM released from the dying neurons, and studies using cell cultures incubated with NM report activation of microglia [106] and inhibition of the ubiqitinproteasome system [107], although we found no effect of NM on indices of cell morphology or survival of primary rat mesencephalic cocultures [51]. In 1992, Gibb [108] noted that the ventral tier of the substantia nigra, in which cell loss is most marked in Parkinsons disease, contains less NM than the heavily pigmented and relatively preserved cells of the dorsal tier.…”

Section: Functional Significance Of the Pigmentsmentioning

confidence: 99%

The comparative biology of neuromelanin and lipofuscin in the human brain

Double

Dedov

Fedorow

et al. 2008

Cell. Mol. Life Sci.

166

157

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Neuromelanin and lipofuscin are two pigments produced within the human brain that, until recently, were considered inert cellular waste products of little interest to neuroscience. Recent research has increased our understanding of the nature and interactions of these pigments with their cellular environment and suggests that these pigments may, indeed, influence cellular function. The physical appearance and distribution of the pigments within the human brain differ, but both accumulate in the aging brain and the pigments share some structural features. Lipofuscin accumulation has been implicated in postmitotic cell aging, while neuromelanin is suggested to function as an iron-regulatory molecule with possible protective functions within the cells which produce this pigment. This review presents comparative aspects of the biology of neuromelanin and lipofuscin, as well as a discussion of their hypothesized functions in brain and their possible roles in aging and neurodegenerative disease.

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“…More recently, iron has been found in the rim of Lewy bodies where α‐synuclein, ubiquitin, and tyrosine hydroxylase (TH) were also present (10). Furthermore, there is also evidence that iron overload facilitates fibrillation of human α‐synuclein and impairs the proteasomal activity (11, 12). Accordingly, pretreatment of R‐apomorphine and EGCG, which possess iron‐chelating properties, has been shown to prevent the increase of α‐synuclein protein in SN (13).…”

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confidence: 99%

Prevention and restoration of lactacystin‐induced nigrostriatal dopamine neuron degeneration by novel brain‐permeable iron chelators

Zhu¹,

Xie

Pan³

et al. 2007

FASEB j.

132

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Dysfunction of the ubiquitin-proteasome system (UPS) and accumulation of iron in substantia nigra (SN) are implicated in the pathogenesis of Parkinson's disease (PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine (DA) neurons. In the present study, we use a new brain-permeable iron chelator, VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline], and its derivative M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor (lactacystin) -induced nigrostriatal degeneration. Bilateral microinjections of lactacystin (1.25 microg/side) into the mouse medial forebrain bundle were performed. Administration of VK-28 (5 mg/kg, once a day) or M30 (5 mg/kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK-28 and M30 both significantly improved behavioral performances and attenuated lactacystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain-permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK-28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD.

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The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells

Cited by 9 publications

References 26 publications

Inhibition of VMAT-2 and DT-Diaphorase Induce Cell Death in a Substantia Nigra-Derived Cell LineAn Experimental Cell Model for Dopamine Toxicity Studies

Inhibition of VMAT-2 and DT-Diaphorase Induce Cell Death in a Substantia Nigra-Derived Cell LineAn Experimental Cell Model for Dopamine Toxicity Studies

The comparative biology of neuromelanin and lipofuscin in the human brain

Prevention and restoration of lactacystin‐induced nigrostriatal dopamine neuron degeneration by novel brain‐permeable iron chelators

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