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Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease.
Neurochem Int. 2006 Apr; 48(5):329-40.NI

Abstract

6-Hydroxydopamine (6-OHDA) is widely used to produce animal models of Parkinson's disease (PD) by selectively destroying the nigro-striatal dopaminergic systems, but selective toxicity of 6-OHDA towards dopaminergic cells in vitro remains controversial. Mutant (A30P and A53T) alpha-synuclein isoforms cause increased vulnerability of cells towards various toxic insults and enhance dopamine transporter (DAT)-mediated toxicity of the selective dopaminergic neurotoxin and mitochondrial complex I inhibitor MPP(+) in vitro. Here we extend our recent studies on DAT-mediated toxicity to elucidate the mechanisms involved in selective dopaminergic toxicity of 6-OHDA. We studied the cytotoxicity as well as the toxic mechanisms of 6-OHDA in human embryonic kidney HEK-293 cells ectopically co-expressing mutant alpha-synucleins and the human DAT protein. 6-OHDA showed half-maximal toxic concentration (TC(50)) of 88 microM in HEK-hDAT cells without alpha-synuclein expression after 24 h, whereas the TC(50) values significantly decreased to 58 and 39 microM by expression of A30P and A53T alpha-synuclein, respectively. alpha-Synuclein expression did not affect 6-OHDA toxicity in HEK-293 cells not expressing the DAT. Analysis of intracellular parameters of cellular energy metabolism revealed that the co-expression of mutant alpha-synucleins in HEK-hDAT cells accelerates the reduction of intracellular net ATP levels and ATP/ADP ratios induced by 6-OHDA. Uptake function of the DAT was not altered by expression of alpha-synuclein isoforms. Our data suggest a mechanism of 6-OHDA-induced dopaminergic toxicity involving an interaction of mutant alpha-synucleins with the DAT molecule and subsequent acceleration of cellular energy depletion that might be relevant for the pathogenesis of PD.

Authors+Show Affiliations

Department of Neurology, University of Ulm, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16406146

Citation

Lehmensiek, Vera, et al. "Dopamine Transporter-mediated Cytotoxicity of 6-hydroxydopamine in Vitro Depends On Expression of Mutant Alpha-synucleins Related to Parkinson's Disease." Neurochemistry International, vol. 48, no. 5, 2006, pp. 329-40.
Lehmensiek V, Tan EM, Liebau S, et al. Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease. Neurochem Int. 2006;48(5):329-40.
Lehmensiek, V., Tan, E. M., Liebau, S., Lenk, T., Zettlmeisl, H., Schwarz, J., & Storch, A. (2006). Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease. Neurochemistry International, 48(5), 329-40.
Lehmensiek V, et al. Dopamine Transporter-mediated Cytotoxicity of 6-hydroxydopamine in Vitro Depends On Expression of Mutant Alpha-synucleins Related to Parkinson's Disease. Neurochem Int. 2006;48(5):329-40. PubMed PMID: 16406146.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease. AU - Lehmensiek,Vera, AU - Tan,Eva-Maria, AU - Liebau,Stefan, AU - Lenk,Thomas, AU - Zettlmeisl,Heinz, AU - Schwarz,Johannes, AU - Storch,Alexander, Y1 - 2006/01/06/ PY - 2005/06/23/received PY - 2005/10/27/revised PY - 2005/11/08/accepted PY - 2006/1/13/pubmed PY - 2006/6/2/medline PY - 2006/1/13/entrez SP - 329 EP - 40 JF - Neurochemistry international JO - Neurochem Int VL - 48 IS - 5 N2 - 6-Hydroxydopamine (6-OHDA) is widely used to produce animal models of Parkinson's disease (PD) by selectively destroying the nigro-striatal dopaminergic systems, but selective toxicity of 6-OHDA towards dopaminergic cells in vitro remains controversial. Mutant (A30P and A53T) alpha-synuclein isoforms cause increased vulnerability of cells towards various toxic insults and enhance dopamine transporter (DAT)-mediated toxicity of the selective dopaminergic neurotoxin and mitochondrial complex I inhibitor MPP(+) in vitro. Here we extend our recent studies on DAT-mediated toxicity to elucidate the mechanisms involved in selective dopaminergic toxicity of 6-OHDA. We studied the cytotoxicity as well as the toxic mechanisms of 6-OHDA in human embryonic kidney HEK-293 cells ectopically co-expressing mutant alpha-synucleins and the human DAT protein. 6-OHDA showed half-maximal toxic concentration (TC(50)) of 88 microM in HEK-hDAT cells without alpha-synuclein expression after 24 h, whereas the TC(50) values significantly decreased to 58 and 39 microM by expression of A30P and A53T alpha-synuclein, respectively. alpha-Synuclein expression did not affect 6-OHDA toxicity in HEK-293 cells not expressing the DAT. Analysis of intracellular parameters of cellular energy metabolism revealed that the co-expression of mutant alpha-synucleins in HEK-hDAT cells accelerates the reduction of intracellular net ATP levels and ATP/ADP ratios induced by 6-OHDA. Uptake function of the DAT was not altered by expression of alpha-synuclein isoforms. Our data suggest a mechanism of 6-OHDA-induced dopaminergic toxicity involving an interaction of mutant alpha-synucleins with the DAT molecule and subsequent acceleration of cellular energy depletion that might be relevant for the pathogenesis of PD. SN - 0197-0186 UR - https://www.unboundmedicine.com/medline/citation/16406146/Dopamine_transporter_mediated_cytotoxicity_of_6_hydroxydopamine_in_vitro_depends_on_expression_of_mutant_alpha_synucleins_related_to_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(05)00269-X DB - PRIME DP - Unbound Medicine ER -