L-DOPA neurotoxicity is mediated by up-regulation of DMT1 - IRE expression

Fang Du; Zhong-Ming Qian; Li Zhu; Xiao Mei Wu; Wing-Ho Yung; Ting-Yuk Tsim; Ya Ke

doi:10.1371/journal.pone.0004593

L-DOPA neurotoxicity is mediated by up-regulation of DMT1 - IRE expression

Fang Du, Zhong-Ming Qian, Li Zhu, Xiao Mei Wu, Wing-Ho Yung, Ting-Yuk Tsim, Ya Ke

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

Background: The mechanisms underlying neurotoxicity caused by L-DOPA are not yet completely known. Based on recent findings, we speculated that the increased expression of divalent metal transporter 1 without iron-response element (DMT1 - IRE) induced by L-DOPA might play a critical role in the development of L-DOPA neurotoxicity. To test this hypothesis, we investigated the effects of astrocyte-conditioned medium (ACM) and siRNA DMT-IRE on L-DOPA neurotoxicity in cortical neurons. Methods and Findings: We demonstrated that neurons treated with L-DOPA have a significant dose-dependent decrease in neuronal viability (MTT Assay) and increase in iron content (using a graphite furnace atomic absorption spectrophotometer), DMT1 - IRE expression (Western blot analysis) and ferrous iron (55Fe(II)) uptake. Neurons incubated in ACM with or without L-DOPA had no significant differences in their morphology, Hoechst-33342 staining or viability. Also, ACM significantly inhibited the effects of L-DOPA on neuronal iron content as well as DMT1 - IRE expression. In addition, we demonstrated that infection of neurons with siRNA DMT-IRE led to a significant decrease in DMT1 - IRE expression as well as L-DOPA neurotoxicity. Conclusion: The up-regulation of DMT1 - IRE and the increase in DMT1 - IRE-mediated iron influx play a key role in L-DOPA neurotoxicity in cortical neurons. © 2009 Du et al.

Original language	English
Article number	e4593
Journal	PLOS ONE
Volume	4
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0004593
Publication status	Published - 25 Feb 2009
Externally published	Yes

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Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

The studies were supported by the Competitive Earmarked Grants of HKRGC (CUHK 466907 - KY), Direct Grant of Chinese University of Hong Kong (A/C: 4450226 - KY and 4450273 - KY), RGC-NSFC Grant (KY), research grants from The Hong Kong Polytechnic University (Niche Area - I - BB8L, GU-384 and G-YG11) and NKLCMMP (Shenzhen), and SZ - HK Innovation Circle Program.

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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title = "L-DOPA neurotoxicity is mediated by up-regulation of DMT1 - IRE expression",

abstract = "Background: The mechanisms underlying neurotoxicity caused by L-DOPA are not yet completely known. Based on recent findings, we speculated that the increased expression of divalent metal transporter 1 without iron-response element (DMT1 - IRE) induced by L-DOPA might play a critical role in the development of L-DOPA neurotoxicity. To test this hypothesis, we investigated the effects of astrocyte-conditioned medium (ACM) and siRNA DMT-IRE on L-DOPA neurotoxicity in cortical neurons. Methods and Findings: We demonstrated that neurons treated with L-DOPA have a significant dose-dependent decrease in neuronal viability (MTT Assay) and increase in iron content (using a graphite furnace atomic absorption spectrophotometer), DMT1 - IRE expression (Western blot analysis) and ferrous iron (55Fe(II)) uptake. Neurons incubated in ACM with or without L-DOPA had no significant differences in their morphology, Hoechst-33342 staining or viability. Also, ACM significantly inhibited the effects of L-DOPA on neuronal iron content as well as DMT1 - IRE expression. In addition, we demonstrated that infection of neurons with siRNA DMT-IRE led to a significant decrease in DMT1 - IRE expression as well as L-DOPA neurotoxicity. Conclusion: The up-regulation of DMT1 - IRE and the increase in DMT1 - IRE-mediated iron influx play a key role in L-DOPA neurotoxicity in cortical neurons. {\textcopyright} 2009 Du et al.",

author = "Fang Du and Zhong-Ming Qian and Li Zhu and Wu, {Xiao Mei} and Wing-Ho Yung and Ting-Yuk Tsim and Ya Ke",

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T1 - L-DOPA neurotoxicity is mediated by up-regulation of DMT1 - IRE expression

AU - Du, Fang

AU - Qian, Zhong-Ming

AU - Zhu, Li

AU - Wu, Xiao Mei

AU - Yung, Wing-Ho

AU - Tsim, Ting-Yuk

AU - Ke, Ya

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2009/2/25

Y1 - 2009/2/25

N2 - Background: The mechanisms underlying neurotoxicity caused by L-DOPA are not yet completely known. Based on recent findings, we speculated that the increased expression of divalent metal transporter 1 without iron-response element (DMT1 - IRE) induced by L-DOPA might play a critical role in the development of L-DOPA neurotoxicity. To test this hypothesis, we investigated the effects of astrocyte-conditioned medium (ACM) and siRNA DMT-IRE on L-DOPA neurotoxicity in cortical neurons. Methods and Findings: We demonstrated that neurons treated with L-DOPA have a significant dose-dependent decrease in neuronal viability (MTT Assay) and increase in iron content (using a graphite furnace atomic absorption spectrophotometer), DMT1 - IRE expression (Western blot analysis) and ferrous iron (55Fe(II)) uptake. Neurons incubated in ACM with or without L-DOPA had no significant differences in their morphology, Hoechst-33342 staining or viability. Also, ACM significantly inhibited the effects of L-DOPA on neuronal iron content as well as DMT1 - IRE expression. In addition, we demonstrated that infection of neurons with siRNA DMT-IRE led to a significant decrease in DMT1 - IRE expression as well as L-DOPA neurotoxicity. Conclusion: The up-regulation of DMT1 - IRE and the increase in DMT1 - IRE-mediated iron influx play a key role in L-DOPA neurotoxicity in cortical neurons. © 2009 Du et al.

AB - Background: The mechanisms underlying neurotoxicity caused by L-DOPA are not yet completely known. Based on recent findings, we speculated that the increased expression of divalent metal transporter 1 without iron-response element (DMT1 - IRE) induced by L-DOPA might play a critical role in the development of L-DOPA neurotoxicity. To test this hypothesis, we investigated the effects of astrocyte-conditioned medium (ACM) and siRNA DMT-IRE on L-DOPA neurotoxicity in cortical neurons. Methods and Findings: We demonstrated that neurons treated with L-DOPA have a significant dose-dependent decrease in neuronal viability (MTT Assay) and increase in iron content (using a graphite furnace atomic absorption spectrophotometer), DMT1 - IRE expression (Western blot analysis) and ferrous iron (55Fe(II)) uptake. Neurons incubated in ACM with or without L-DOPA had no significant differences in their morphology, Hoechst-33342 staining or viability. Also, ACM significantly inhibited the effects of L-DOPA on neuronal iron content as well as DMT1 - IRE expression. In addition, we demonstrated that infection of neurons with siRNA DMT-IRE led to a significant decrease in DMT1 - IRE expression as well as L-DOPA neurotoxicity. Conclusion: The up-regulation of DMT1 - IRE and the increase in DMT1 - IRE-mediated iron influx play a key role in L-DOPA neurotoxicity in cortical neurons. © 2009 Du et al.

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DO - 10.1371/journal.pone.0004593

M3 - RGC 21 - Publication in refereed journal

C2 - 19240805

SN - 1932-6203

VL - 4

JO - PLOS ONE

JF - PLOS ONE

IS - 2

M1 - e4593

ER -

L-DOPA neurotoxicity is mediated by up-regulation of DMT1 - IRE expression

Abstract

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