Vesicular Uptake Blockade Generates the Toxic Dopamine Metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 Cells: Relevance to the Pathogenesis of Parkinson's Disease

J Neurochem. 2012 Dec;123(6):932-43. doi: 10.1111/j.1471-4159.2012.07924.x. Epub 2012 Oct 25.

Abstract

Parkinson's disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intraneuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, as α-synuclein oligomers may be pathogenetic in Parkinson's disease, oligomerizes α-synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPAL-daidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F- or (13) C-dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL--induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L-aromatic-amino-acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 95-97% and rapidly increased cell DOPAL content (p = 0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p = 0.004). Intracellular DOPAL contributed to dopamine-evoked apoptosis and DOPA-evoked synuclein dimerization. The findings fit with the 'catecholaldehyde hypothesis,' according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson's disease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analogs & derivatives*
  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • 3,4-Dihydroxyphenylacetic Acid / toxicity
  • Animals
  • Cytoplasmic Vesicles / drug effects*
  • Cytoplasmic Vesicles / metabolism*
  • Dopamine / deficiency
  • Dopamine / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • PC12 Cells
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / etiology
  • Parkinsonian Disorders / metabolism*
  • Rats

Substances

  • 3,4-Dihydroxyphenylacetic Acid
  • 3,4-dihydroxyphenylacetaldehyde
  • Dopamine