Consequences of impaired purine recycling in dopaminergic neurons

Abstract

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.

Lesch-Nyhan disease: from mechanism to model and back again

“…In addition to revealing many of the same changes found in primary source cells, these models have revealed abnormalities that could not be identified with non-neural cells. HPRT-deficient dopamine neuronlike lines show a loss of dopamine content that is analogous to that reported for the LND brain (Bitler and Howard, 1986;Yeh et al, 1998;Lewers et al, 2008). These models also reveal changes in neuronal microstructure in the form of abnormal numbers or morphology of neurites, which are comparable to dendrites or axons in vivo (Stacey et al, 1999;Connolly et al, 2001;Shirley et al, 2007).…”

“…Neuroimaging studies of affected patients reveal similar reductions in other markers of dopamine neurons in the same region (Ernst et al, 1996;Wong et al, 1996). The reasons for the selective dysfunction of dopamine pathways of the basal ganglia are unknown, although there is probably a developmental defect Lewers et al, 2008).…”

“…A final limitation is that findings might be idiosyncratic to the cell model being evaluated (Shirley et al, 2007;Lewers et al, 2008). Because LND is so rare, models derived from blood samples or fibroblast biopsies often come from a single patient, or very small numbers of patients.…”

“…Further, modeling should not be viewed as an objective with fixed criteria that are used to define success or failure, but rather as an iterative process wherein information gained is re-invested to modify the starting model or to generate new ones that are even more informative. For example, several currently available cell and animal models have pointed to a defect in developmental specification of the neurochemical phenotype of dopamine neurons in HPRT deficiency Lewers et al, 2008). These studies have pointed to the need for models of dopamine neuron development in which the influence of HPRT deficiency can be studied more dynamically.…”

II: Effects of a dopamine receptor antagonist on fathead minnow dominance behavior and ovarian gene expression in the fathead minnow and zebrafish

“…Some intriguing links between defects in purine recycling and degeneration of dopaminergic neurons have been observed (Egami et al, 2007;Lewers et al, 2008). In mammals, defects in hypoxanthine-guanine phosphoribosyl transferase (hprt), a purine recycling enzyme, are linked to dopamine loss associated with several diseases (Egami et al, 2007;Lopez, 2008).…”