Consequences of impaired purine recycling in dopaminergic neurons.
A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.
Lewers
J C
JC
Department of Neurology, Meyer Room 6-181, 600 North Wolfe Street, Johns Hopkins University, Baltimore, MD 21287, USA.
Ceballos-Picot
I
I
Shirley
T L
TL
Mockel
L
L
Egami
K
K
Jinnah
H A
HA
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002461:Cell Line, Transformed; D004298:Dopamine / Q000096:biosynthesis / Q000172:deficiency*; D004734:Energy Metabolism / Q000235:genetics; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D011687:Purines / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D004798:Enzymes; D011687:Purines; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D007041:Hypoxanthine Phosphoribosyltransferase; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine