No abstract

The brain of the adult fruit fly, Drosophila melanogaster, contains tyrosine hydroxylase, the rate-limiting enzyme required for catecholamine biosynthesis, as well as dopa decarboxylase. Catecholamines, principally dopamine, are also present. We have previously shown that pharmacological inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine results in a dose-related inhibition of locomotor activity in adult organisms. Similar results were found with reserpine, a well-known inhibitor of catecholamine uptake into storage granules. The drug-induced inhibition could be prevented in each case by the concomitant administration of L-dopa. The single-copy gene coding for tyrosine hydroxylase in Drosophila is pale (ple). Both null and temperature-sensitive loss of function mutant alleles of ple are recessive embryonic lethals. Heterozygous null mutant flies have normal locomotor activity demonstrating that only a single dose of the wild type form of ple is required to support normal function. Both hemizygous and homozygous temperature-sensitive ple mutants (ple(ts1)) also show normal locomotor activity at the permissive temperature for this mutant allele (18 degrees C), which progressively declines as the temperature is increased to its restrictive level (29 degrees C). These abnormal locomotor effects are reversible by L-dopa. Thus the effects on locomotor activity resulting from the pharmacological inhibition of catecholamine synthesis or storage are the same as those resulting from lack of tyrosine hydroxylase expression. These findings indicate that brain catecholamine loss decreases locomotor activity in the fly, as it does in mammals, and demonstrate the ability of functional genomic studies to mimic that of pharmacological inhibition of enzyme function or other similar processes.

We ascertained a patient with the full-blown phenotype of isolated sulfite oxidase deficiency in a consanguineous Arab family. The proband's phenotype included the presence of intractable seizures in the neonatal period, some dysmorphic features, neuroradiologic findings reminiscent of hypoxic ischemic encephalopathy and rapidly progressive brain destruction leading to severe neurodevelopmental impairment. Biochemically, the patient excreted a large amount of S-sulfocysteine with normal amounts of xanthene and hypoxanthine and had normal plasma uric acid, which was consistent with isolated sulfite oxidase deficiency. We report the identification of the first Arab mutation in SUOX, the gene for sulfite oxidase enzyme, in the ascertained family. The newly identified Arab mutation in the SUOX gene (a single nucleotide deletion, del G1244) is predicted to cause a frame shift at amino acid 117 of the translated protein with the generation of a stop codon and total truncation of the molybdo-pterin- and the dimerizing-domain(s) of SUOX protein expressed from the mutant allele. The identification of this new Arab SUOX mutation should facilitate pre-implantation genetic diagnosis and selection of unaffected embryos for future pregnancy in the ascertained family with the mutation and related families with the same mutation.

No abstract

Inhibition of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, by α-methyl-p-tyrosine (αMT) at media concentrations of 0.3-3.0 mM, markedly inhibited (>90%) fly reproduction and development as evidenced by progeny count. Under these conditions adult spontaneous locomotor activity (SMA) was also dose-dependently reduced. However, no significant effects on behavior were observed at 0.3 mM. The behavioral effects of αMT were prevented by coadministration of L-DOPA. Similar effects on behavior and development were produced by reserpine at doses of 0.1-1.0 mM. The higher doses affected behavior, but no behavioral effects occurred at 0.1 mM. Rescue from the effects of reserpine was also achieved with L-DOPA. Treatment at 1 mM with the mammalian catecholamine receptor blockers propranolol (β 1 β 2 ), raclopride (D 2 ), SK&F 83566 (D 1 ), prazosin (α 1 ), and rauwolscine (α 2 ) did not affect behavior. The two α adrenoceptor inhibitors, however, markedly decreased fly development. These results suggest that the receptor mechanisms mediating the effects of catecholamines on behavior and development are different. The locomotor behavior of adult progeny of parents treated with the lowest doses of αMT and reserpine described above was markedly suppressed by these drug treatments. This result indicates an increased sensitivity of the progeny to compounds which share the ability to deplete tissue catecholamines. Thus, alterations in catecholamine function during development may have behavioral consequences in surviving organisms. Drug Dev.