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. 2017 Feb:35:88-91.
doi: 10.1016/j.parkreldis.2016.12.011. Epub 2016 Dec 15.

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

David S Goldstein  1 , Patti Sullivan  2 , Courtney Holmes  2 , Deborah C Mash  3 , Irwin J Kopin  2 , Yehonatan Sharabi  4
Affiliations

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

David S Goldstein et al. Parkinsonism Relat Disord. 2017 Feb.

Erratum in

Abstract

Background: Severe putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA.

Methods: Post-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA).

Results: The PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01).

Interpretation: Based on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases.

Keywords: Cysteinyl-DOPA; Cysteinyl-dopamine; Multiple system atrophy; Parkinson’s disease.

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Conflict of interest statement

Conflicts of interest

The Authors have no conflicts of interest to disclose.

Figures

Fig. 1.
Fig. 1.. Concept diagram about sources and metabolic fate of dopamine in putamen tissue.
Tyrosine hydroxylase (TH) catalyzes the conversion of tyrosine to DOPA, and L-aromatic-amino-acid decarboxylase (LAAAD) converts DOPA to dopamine (DA). Most of the DA in putamen tissue is in vesicles, due to uptake mediated by the vesicular monoamine transporter (VMAT). Cytoplasmic DA can be metabolized by monoamine oxidase (MAO) in the outer mitochondrial membrane to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolize by aldehyde dehydrogenase (ALDH) to form 3,4-dihydroxyphenylacetic acid (DOPAC) or by aldehyde/aldose reductase (AR) to form 3,4-dihydroxyphenylethanol (DOPET). Cytoplasmic DA can oxidize spontaneously to form DA-quinone (DA-Q) and then 5-S-cysteinyl-DA (Cys-DA), and cytoplasmic DOPA can oxidize spontaneously to form DOPA-quinone (DOPA-Q) and then 5-S-cysteinyl-DOPA (Cys-DOPA). The rectangle in aqua corresponds to products of TH proximal to DA; in pink to cytoplasmic DA metabolites; and in green to vesicular DA.
See this image and copyright information in PMC

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