Effects of Pharmacological Agents upon a Transgenic Model of Parkinson's Disease in Drosophila melanogaster

Abstract

The human gene that codes for the protein ␣-synuclein has been transferred into the Drosophila melanogaster genome. The transgenic flies recapitulate some of the essential features of Parkinson's disease. These include the degeneration of certain dopaminergic neurons in the brain accompanied by the appearance of age-dependent abnormalities in locomotor activity. In the present study, we tested the locomotor response of these transgenic flies to prototypes of the major classes of drugs currently used to treat this disorder. A time course study was first conducted to determine when impaired locomotor activity appeared relative to normal "wild-type" flies. A climbing or negative geotaxis assay measuring the ability of the organisms to climb up the walls of a plastic vial was used. Based on the results obtained, normal and transgenic flies were treated with each of the drugs in their food for 13 days and then assayed. The activity of transgenic flies treated with L-DOPA was restored to normal. Similarly, the dopamine agonists pergolide, bromocriptine, and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-

Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine

“…11,12,53,71 However, while the enzymes required for DA synthesis are expressed both in the nervous system and in cuticle-forming tissue, DVMAT is more specifically expressed in neurons. 30 Furthermore, consistent with the notion that DVMAT is not required for cuticle formation, we show here that larval development is relatively insensitive to the inhibition with reserpine, and we suggest that DVMAT may be particularly useful for studying the neuronal functions of monoamines.…”

“…Since previous pharmacologic experiments suggest that sexual behavior and fertility also may involve DA, 11,12,52,53,65 we tested the effects of haloperidol on fertility. Haloperidol administration appeared to increase fertility in DVMAT overexpressing flies.…”

“…We also find that treatment of adult flies with reserpine decreases the number of adult progeny produced by wild-type flies at concentrations as low as 1 mM (Figure 3c), consistent with other reports similarly investigating the effects of this and other aminergic agents on fertility. 52,53 In addition, we directly tested the effects of reserpine on larval development by transferring 30 freshly laid embryos to food containing increasing concentrations of drug. Although 1000 mM reserpine had a significant effect Green circles in the cartoon indicate serotonergic cells that localize to previously identified clusters 5 in the superior protocerebrum (SP 1 , SP 2 ), the lateral protocerebrum (LP 1 , LP 2 ), the inferior medial protocerebrum (IP) and the subesophageal ganglion (s.e.)…”

ADrosophilaModel of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine

“…Others, using rotenone (Pendleton et al, 2002;Coulom and Birman, 2004) or ␣-synuclein to model PD in the fly, have shown that enhancing DA synthesis, and presumably release, can rescue the phenotype caused by DA cell loss without necessarily decreasing the degeneration of DA cells (Coulom and Birman, 2004). In these cases, as in the symptomatic treatment of PD, increased release by the remaining cells presumably compensates for the death of other DA neurons.…”

Successes of Modelling Parkinson Disease in Drosophila

“…Of great importance, experiments where the loss of neurons is correlated to the loss of locomotor ability over time have provided sufficient comparison. For example, when oxidative stress is prevented, the loss of locomotor activity and the loss of dopaminergic neurons are diminished together in flies expressing alpha-synuclein (Pendleton et al, 2002, Yang et al, 2003, Wassef et al, 2007, Botella et al, 2008. As such, the loss of climbing ability seems to be a meaningful and modifiable phenotype that allows for the detection and validation of subtle influences.…”