Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy |
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| Affiliation: | 1. Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, MD 20892-1620, USA;2. University of Miami Miller School of Medicine, Miami, FL 33136, USA;3. Chaim Sheba Medical Center, Tel Ha-Shomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;1. School of Medicine, University of New South Wales, Sydney, Australia;2. Department of Neurology, St Vincent''s Hospital, Sydney, Australia;1. Department of Neurosurgery, Medical University of Vienna, Vienna, Austria;2. Institute of Neurology, Medical University of Vienna, Vienna, Austria;3. Medical University of Vienna, Department of Medicine II, Division of Angiology, Vienna, Austria;4. Department of Neurology, Medical University of Vienna, Vienna, Austria;5. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada;6. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;7. Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada;1. Orthopaedic and Traumatology Department of Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Indonesia;2. Orthopaedic and Traumatology Resident of Faculty of Medicine, Universitas Indonesia, Indonesia;1. Service de Neurologie, CHU de Bordeaux, F-33076 Bordeaux, France;2. Department of Clinical Neurophysiology, University Hospital Bordeaux, France;3. CNRS, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS UMR 5287, Université de Bordeaux, Bordeaux, France;4. CHU de Bordeaux, Unité de Soutien Méthodologique à la Recherche Clinique (USMR), Pôle de santé publique, Bordeaux, France;5. Univ. Bordeaux, Sommeil, Attention et Neuropsychiatrie, USR 3413, F-33000 Bordeaux, France;6. CNRS, Sommeil, Attention et Neuropsychiatrie, USR 3413, F-33000 Bordeaux, France;7. Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France;8. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France;9. Centre de référence atrophie multisystématisée, CHU de Bordeaux, F-33076 Bordeaux, France |
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| Abstract: | BackgroundSevere 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.MethodsPost-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).ResultsThe 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).InterpretationBased 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. |
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| Keywords: | Cysteinyl-dopamine Cysteinyl-DOPA Parkinson’s disease Multiple system atrophy ALDH" },{" #name" :" keyword" ," $" :{" id" :" kwrd0035" }," $$" :[{" #name" :" text" ," _" :" aldehyde dehydrogenase DA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" dopamine DHPG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" 3,4-dihydroxyphenylglycol DOPAC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" 3,4-dihydroxyphenylacetic acid DOPAL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" 3,4-dihydroxyphenylacetaldehyde DOPET" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" 3,4-dihydroxyphenylethanol MSA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" Multiple system atrophy NE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" norepinephrine PD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" Parkinson’s disease VMAT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" vesicular monoamine transporter |
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