Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease

David S. Goldstein, Patti Sullivan, Courtney Holmes, Gary W. Miller, Shawn Alter, Randy Strong, Deborah C Mash, Irwin J. Kopin, Yehonatan Sharabi

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the 'catecholaldehyde hypothesis,' DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson's disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase (ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA: DOPA concentration ratio indicates vesicular uptake, and the 3,4- dihydroxyphenylacetic acid: DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001), and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH. According to the 'catecholaldehyde hypothesis,' the toxic dopamine metabolite DOPAL contributes to loss of striatal dopaminergic innervation in Parkinson's disease. Here we provide post-mortem neurochemical evidence that in Parkinson's disease patients, putamen DOPAL buildup reflects decreased vesicular sequestration of cytosolic dopamine and decreased DOPAL metabolism by aldehyde dehydrogenase. The results fit with an intra-neuronal autotoxic mechanism of Parkinson's disease. According to the 'catecholaldehyde hypothesis,' the toxic dopamine metabolite DOPAL contributes to loss of striatal dopaminergic innervation in Parkinson's disease. Here we provide post-mortem neurochemical evidence that in Parkinson's disease patients, putamen DOPAL buildup reflects decreased vesicular sequestration of cytosolic dopamine and decreased DOPAL metabolism by aldehyde dehydrogenase. The results fit with an intra-neuronal autotoxic mechanism of Parkinson's disease.

Original languageEnglish
Pages (from-to)591-603
Number of pages13
JournalJournal of Neurochemistry
Volume126
Issue number5
DOIs
StatePublished - Sep 1 2013

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Poisons
Metabolites
Parkinson Disease
Dopamine
Aldehyde Dehydrogenase
Putamen
Vesicular Monoamine Transport Proteins
Metabolism
Corpus Striatum
3,4-Dihydroxyphenylacetic Acid
3,4-dihydroxyphenylacetaldehyde
Catechols
Detoxification
Gene Knockout Techniques
Gene encoding
Transgenic Mice

Keywords

  • DOPAC
  • DOPAL
  • dopamine
  • DOPET
  • monoamine oxidase
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Goldstein, D. S., Sullivan, P., Holmes, C., Miller, G. W., Alter, S., Strong, R., ... Sharabi, Y. (2013). Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. Journal of Neurochemistry, 126(5), 591-603. https://doi.org/10.1111/jnc.12345

Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. / Goldstein, David S.; Sullivan, Patti; Holmes, Courtney; Miller, Gary W.; Alter, Shawn; Strong, Randy; Mash, Deborah C; Kopin, Irwin J.; Sharabi, Yehonatan.

In: Journal of Neurochemistry, Vol. 126, No. 5, 01.09.2013, p. 591-603.

Research output: Contribution to journalArticle

Goldstein, DS, Sullivan, P, Holmes, C, Miller, GW, Alter, S, Strong, R, Mash, DC, Kopin, IJ & Sharabi, Y 2013, 'Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease', Journal of Neurochemistry, vol. 126, no. 5, pp. 591-603. https://doi.org/10.1111/jnc.12345
Goldstein DS, Sullivan P, Holmes C, Miller GW, Alter S, Strong R et al. Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. Journal of Neurochemistry. 2013 Sep 1;126(5):591-603. https://doi.org/10.1111/jnc.12345
Goldstein, David S. ; Sullivan, Patti ; Holmes, Courtney ; Miller, Gary W. ; Alter, Shawn ; Strong, Randy ; Mash, Deborah C ; Kopin, Irwin J. ; Sharabi, Yehonatan. / Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease. In: Journal of Neurochemistry. 2013 ; Vol. 126, No. 5. pp. 591-603.
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