Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease

Abstract

Transgenic Drosophila expressing human α-synuclein faithfully replicate essential features of human parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in α-synuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with α-synuclein expression. Most importantly, at the presymptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of α-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.