Lifetime Proteomic Profiling of an A30P α-SynucleinDrosophilaModel of Parkinson's Disease

Abstract

A survey of the proteome changes in an A30P alpha-synuclein Drosophila model of Parkinson's disease (PD) in comparison to age-matched controls is presented for seven different ages across the adult lifespan. The data were acquired by a shotgun proteomic approach that involves multidimensional liquid chromatographies coupled to mass spectrometry and database searching techniques. Semiquantitative analysis to assess relative changes in protein expression between the Drosophila PD model and age-matched controls provides evidence that 28, 19, 12, 5, 7, 23, and 17 proteins are significantly differentially expressed at days 1, 10, 20, 30, 40, 50, and 60, respectively. From the experimental approach employed, it appears that most dysregulated proteins are associated with narrow distributions of ages, such that disease-associated differences change substantially across the lifespan. Previous measurements [J. Proteome Res. 2007, 6, 348] at days 1, 10, and 30 showed dysregulation of actin cytoskeletal proteins at day 1 and mitochondrial proteins at day 10, suggesting that defects in the actin cytoskeleton and the mitochondria are associated with dopaminergic neuron degeneration in PD. Analysis of the day 20, 40, 50, and 60 animals supports the finding that these cytoskeletal and mitochondrial changes predominate in the youngest (pre-symtomatic and early disease stages) animals. Although studies across many time points appear to be important for characterizing disease state, an understanding of molecular changes at the youngest ages should be most important for addressing causation.