Journal
JOURNAL OF NEURAL TRANSMISSION
Volume 108, Issue 12, Pages 1363-1374Publisher
SPRINGER-VERLAG WIEN
DOI: 10.1007/s007020100013
Keywords
Parkinson's disease; 5-S-cysteinyldopamine; DHBT-1; pyruvate dehydrogenase complex
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Funding
- NIGMS NIH HHS [GM32367] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM032367] Funding Source: NIH RePORTER
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The principal neuropathological feature of Parkinson's disease is the degeneration of melanized dopamine neurons in the substantia nigra pars compacta (SNc). Characteristic pathobiochemical changes in the parkinsonian SNc include a fall of both dopamine (DA) and glutathione levels (GSH), increased activity of gamma -glutamyl transpeptidase, a key enzyme involved in the degradation of GSH to L-cysteine (CySH), together with evidence for elevated intraneuronal superoxide (O-2(-.)), nitric oxide (NO .) and thence peroxynitrite (ONOO-) generation, and accelerated DA oxidation as indicated by a large rise of the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA concentration ratio. The latter effect is consistent with an increased rate of DA oxidation by O-2(-.) and ONOO- forming DA-o-quinone which reacts with CySH forming 5-S-CyS-DA. However, 5-S-CyS-DA is readily further oxidized to 7-(2-aminoethyl)-3,4-diliydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 is rapidly accumulated by isolated intact rat brain mitochondria and selectively inhibits complex if respiration and the alpha -ketoglutarate dehydrogenase (alpha -KGDH) complex. In this study it is demonstrated that DHBT-1 also inhibits the pyruvate dehydrogenase complex (PDHC). The mechanism underlying the inhibition of all of these enzyme complexes involves bioactivation of intramitochondrial DHBT-1 by oxidation to highly electrophilic metabolites that covalently bind to active site cysteine residues. Thus, oxidative metabolites of intraneuronal 5-S-CyS-DA may contribute to impaired mitochondrial complex I and alpha -KGDH activities known to occur in the parkinsonian SNc and suggest that impaired PDHC evoked by the same metabolites may also occur in PD.
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