Selective dopaminergic vulnerability: 3,4-dihydroxyphenylacetaldehyde targets mitochondria.
Parkinson's disease (PD) is a major cause of age-related morbidity and mortality, present in nearly 1% of individuals at ages 70-79 and approximately 2.5% of individuals at age 85. L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression. Association between mitochondrial dysfunction, monoamine oxidase (MAO) activity, and dopaminergic neurotoxicity has been repeatedly observed, but the mechanisms underlying selective dopaminergic neuron depletion in aging and neurodegenerative disorders remain unclear. We now report that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the MAO metabolite of dopamine, is more cytotoxic in neuronally differentiated PC12 cells than dopamine and several of its metabolites. In isolated, energetically compromised mitochondria, physiological concentrations of DOPAL induced the permeability transition (PT), a trigger for cell death. Dopamine was > 1000-fold less potent. PT inhibitors protected both mitochondria and cells against DOPAL. Sensitivity to DOPAL was reduced > or = 30-fold in fully energized mitochondria, suggesting that mitochondrial respiration may increase resistance to PT induction by the endogenous DOPAL in the substantia nigra. These data provide a potential mechanism of action for L-DOPA-mediated neurotoxicity and suggest two potentially interactive mechanisms for the selective vulnerability of neurons exposed to dopamine.
Kristal
B S
BS
Dementia Research Service, Burke Medical Research Institute, White Plains, NY 10605, USA. bkristal@burke.org
Conway
A D
AD
Brown
A M
AM
Jain
J C
JC
Ulluci
P A
PA
Li
S W
SW
Burke
W J
WJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D062365:Aminobenzoates; D000818:Animals; D034341:Aristolochic Acids; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012119:Respiration / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D062366:para-Aminobenzoates
D062365:Aminobenzoates; D034341:Aristolochic Acids; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010616:Phenanthrenes; D014475:Uncoupling Agents; D062366:para-Aminobenzoates; D012402:Rotenone; D015102:3,4-Dihydroxyphenylacetic Acid; D014268:Trifluoperazine; C007430:3,4-dihydroxyphenylacetaldehyde; D016572:Cyclosporine; D020932:Nerve Growth Factor; C000228:aristolochic acid I; D010129:4-Aminobenzoic Acid; D004298:Dopamine; C073325:butacaine