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

David S. Goldstein, Patti Sullivan, Courtney Holmes, Deborah C Mash, Irwin J. Kopin, Yehonatan Sharabi

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)88-91
Number of pages4
JournalParkinsonism and Related Disorders
Volume35
DOIs
StatePublished - Feb 1 2017

Fingerprint

Cysteinyldopa
Multiple System Atrophy
Catechols
Putamen
Denervation
Parkinson Disease
Dopamine
Aromatic-L-Amino-Acid Decarboxylases
3,4-Dihydroxyphenylacetic Acid
Hydroxylation

Keywords

  • Cysteinyl-DOPA
  • Cysteinyl-dopamine
  • Multiple system atrophy
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy. / Goldstein, David S.; Sullivan, Patti; Holmes, Courtney; Mash, Deborah C; Kopin, Irwin J.; Sharabi, Yehonatan.

In: Parkinsonism and Related Disorders, Vol. 35, 01.02.2017, p. 88-91.

Research output: Contribution to journalArticle

Goldstein, David S. ; Sullivan, Patti ; Holmes, Courtney ; Mash, Deborah C ; Kopin, Irwin J. ; Sharabi, Yehonatan. / Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy. In: Parkinsonism and Related Disorders. 2017 ; Vol. 35. pp. 88-91.
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T1 - Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

AU - Goldstein, David S.

AU - Sullivan, Patti

AU - Holmes, Courtney

AU - Mash, Deborah C

AU - Kopin, Irwin J.

AU - Sharabi, Yehonatan

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

KW - Cysteinyl-DOPA

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