While the remarkable degree with which the phenotypes associated with PD appear to be recapitulated in a-synuclein-expressing transgenic Drosophila have made this an attractive model for studies of PD pathogenesis, it is important to point out that several key features of this disease model have not been reliably replicated. One of the earliest conflicts concerns the locomotor defect of a-synuclein expressing flies. At present, only half of the studies that have examined locomotor ability in a-synuclein transgenic flies were able to detect a climbing defect associated with a-synuclein expression (41,44,57,58). While these conflicts are not easily reconciled, several possible explanations can be offered. One potential source of variation in studies examining climbing behavior in flies relates to methodology. The finding that dopamine neuron dysfunction results in a hyperexcitable or startle phenotype upon vigorous mechanical disturbance of flies raises the possibility that the intensity of tapping flies to the bottom of a vial may impact the outcome of a climbing assay (33). Thus, the results of a climbing assay may vary among individual researchers because vigorous tapping of vials might induce a startle response that would manifest as a climbing defect in response to dopamine neuron loss, whereas milder handling might fail to induce the startle response. Another possible source of variation in climbing behavior relates to recent work demonstrating that apparently homogeneous fly populations consist of subpopulations with either "high" or "low" locomotor activity (35). Failing to account for this phenomenon could result in situations in which there are an excess of a-synuclein expressing flies in the low locomotor activity state relative to the control population.
Recently, a more concerning challenge to the a-synuclein transgenic model was raised in a report by Pesah et al. (58) which failed to detect evidence of loss of dopamine neurons. These investigators were also unable to document retinal degeneration despite using the same WT a-synuclein transgenic lines reported by other investigators to cause neuronal loss. The inability of these investigators to detect neuron loss is independently supported by our own work with these same a-synuclein transgenic lines. Moreover, we also find that an A30P mutationally altered a-synuclein transgenic line fails to induce loss of TH-positive neurons (Table 2).
A recent study by Auluck et al. (59) strongly suggests that the conflicting results of dopamine neuron analysis in a-synuclein transgenic flies are likely explained by differences in the methodology used to analyze dopamine neurons. While all of the studies that documented neuronal loss in a-synuclein-expressing flies utilized paraffin embedded sectioning and light microscopy techniques to visualize: TH-positive neurons, the conflicting studies of Pesah et al. (and our own work) involved the use of confocal microscopy of whole-mount brains to detect TH-positive neurons. Thus, one possible explanation for these conflicting results is
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