GTP cyclohydrolase I induction in striatal astrocytes following intrastriatal kainic acid lesion.
The cause of premature death of dopamine neurons in patients with Parkinson's disease remains unknown. It is speculated that damaging reactive species resulting from the metabolism of dopamine, nitric oxide, and tetrahydrobiopterin (BH(4)) may be involved. GTP cyclohydrolase I (GCH1) is the first and rate-limiting enzyme in the synthesis of BH(4), an essential cofactor for tyrosine hydroxylase and nitric oxide synthase in dopamine and nitric oxide production, respectively. Our studies have explored BH(4) metabolism in the nigrostriatal system following intrastriatal kainic acid lesion. We have demonstrated that 1 week following kainic acid there was an increase in striatal GCH1 mRNA, protein, and activity. There was also an elevation of BH(4) levels in the striatum. Part of the induction of GCH1 was localized in situ to astrocytes. Further, the striatal lesion caused death of both neurons and astrocytes in striatum, as shown by in situ end labeling. These novel observations suggest that the induction of GTP cyclohydrolase and BH(4) in striatal astrocytes may be mediating death of striatal neuronal and non-neuronal cells. This work supports existing and emerging reports that demonstrate the importance of dopamine metabolism in neuronal death of the nigrostriatal system.
Foster
Jane A
JA
William T Gossett Neurology Laboratories, Henry Ford Health System, 1 Ford Place, 4D, Detroit, MI 48202, USA. jaf@codon.nih.gov
Christopherson
Patricia L
PL
Levine
Robert A
RA
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D016923:Cell Death / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006136:GTP Cyclohydrolase / Q000096:biosynthesis*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D016716:PC12 Cells; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D006136:GTP Cyclohydrolase; D007608:Kainic Acid