Drosophila models of Parkinson's disease: discovering relevant pathways and novel therapeutic strategies

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.

Figure 1

Representative phenotypes found in different Drosophila PD models. (a)–(d) DA neuron loss detected in Drosophila adult brains by immunostainings with anti-TH antibody, which specifically recognizes these neurons, in paraffin sections (a, b) or whole-mount brains (c, d). A reduction in the number of DA neurons is observed in both Ddc-GAL4/DJ-1α RNAi (b) [50] and Ddc-GAL4/UAS-α-Synuclein (d) [51] brains when compared to age-matched Ddc-GAL4/+ controls (a, c). (e)–(j) Examples of phenotypes observed in parkin LOF mutants (f, h, j) compared to controls (e, g, i). They include downturned wings (f), muscle degeneration (h), and abnormal mitochondrial morphology (j) [52]. (k) Premature loss of climbing ability in transgenic flies expressing wild-type, A30P, and A53T mutant forms of α-Synuclein [34]. (l) Reduced lifespan of DJ-1β mutants compared to y, w control flies cultured under the same conditions. (m) Elevated sensitivity to paraquat stress in DJ-1αand DJ-1β mutant flies, represented by calculating the percentage of dead flies after feeding 15 mM for 18 h [53]. (n)–(o) Quantification of oxidative stress levels in 1-2-day-old DJ-1β mutants and age-matched y, w control flies. DJ-1β mutants show an increase in lipid peroxidation (LPO) product malondialdehyde (MDA) (n). Catalase (CAT) enzymatic activity is also increased (o) [54].