While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson’s disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tauE14. Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1105-x) contains supplementary material, which is available to authorized users.

Several large or mid-scale collections of Drosophila enhancer traps have been recently created to allow for genetic swapping of GAL4 coding sequences to versatile transcription activators or suppressors such as LexA, QF, split-GAL4 (GAL4-AD and GAL4-DBD), GAL80 and QS. Yet a systematic analysis of the feasibility and reproducibility of these tools is lacking. Here we focused on InSITE GAL4 drivers that specifically label different subpopulations of olfactory neurons, particularly local interneurons (LNs), and genetically swapped the GAL4 domain for LexA, GAL80 or QF at the same locus. We found that the major utility-limiting factor for these genetic swaps is that many do not fully reproduce the original GAL4 expression patterns. Different donors exhibit distinct efficacies for reproducing original GAL4 expression patterns. The successfully swapped lines reported here will serve as valuable reagents and expand the genetic toolkits of Drosophila olfactory circuit research.