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

David Vauzour, John T Pinto, Arthur J L Cooper, Jeremy P E Spencer

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13 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)41-52
Number of pages12
JournalBiochemical Journal
Issue number1
Publication statusPublished - 1 Oct 2014


  • mitogen-activted protein kinase (MAPK)neurotoxicityParkinson’s disease (PD)primary neuron5-S-cysteinyldopamine (CysDA)

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