The neurotoxicity of 5-S-cysteinyldopamine is mediated by the early activation of ERK1/2 followed by the subsequent activation of ASK-1/JNK1/2 pro-apoptotic signalling

Vauzour, David, Pinto, John T, Cooper, Arthur J L and Spencer, Jeremy P E (2014) The neurotoxicity of 5-S-cysteinyldopamine is mediated by the early activation of ERK1/2 followed by the subsequent activation of ASK-1/JNK1/2 pro-apoptotic signalling. Biochemical Journal, 463 (1). pp. 41-52. ISSN 0264-6021

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Abstract

Parkinson's disease is characterized by the progressive and selective loss of dopaminergic neurons in the substantia nigra. It has been postulated that endogenously formed 5-S-cysteinyldopamine (CysDA) and its metabolites may be, in part, responsible for this selective neuronal loss, although the mechanisms by which they contribute to such neurotoxicity are not understood. Exposure of neurons in culture to CysDA caused cell injury, apparent 12-48 h post-exposure. A portion of the neuronal death induced by CysDA was preceded by a rapid uptake and intracellular oxidation of CysDA, leading to an acute and transient activation of ERK2 and caspase 8. The oxidation of CysDA also induced the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser-967, the phosphorylation of c-jun N-terminal kinase (JNK) and c-Jun (Ser-73) as well as the activation of p38, caspase 3, caspase 8, caspase 7 and caspase 9. Concurrently, the inhibition of complex I by the dihydrobenzothiaine DHBT-1, formed from the intracellular oxidation of CysDA, induces complex I inhibition and the subsequent release of cytochrome c which further potentiates pro-apoptotic mechanisms. Our data suggest a novel, comprehensive mechanism for CysDA that may hold relevance for the selective neuronal loss observed in Parkinson's disease.

Item Type: Article
Uncontrolled Keywords: mitogen-activted protein kinase (mapk)neurotoxicityparkinson’s disease (pd)primary neuron5-s-cysteinyldopamine (cysda)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 15 Sep 2014 12:18
Last Modified: 21 Apr 2020 23:23
URI: https://ueaeprints.uea.ac.uk/id/eprint/50020
DOI: 10.1042/BJ20131519

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