Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision.

Ryan J.H West,Alex R Wade,Christopher J.H Elliott

doi:10.1038/srep16933

Abstract

Electrophysiological studies indicate altered contrast processing in some Parkinson’s Disease (PD) patients. We recently demonstrated that vision is altered in Drosophila PD models and hypothesised that different types of genetic and idiopathic PD may affect dopaminergic visual signalling pathways differently. Here we asked whether visual responses in Drosophila could be used to identify PD mutations. To mimic a clinical setting a range of flies was used. Young flies from four control lines were compared to three early-onset PD mutations (PINK1, DJ-1α and DJ-1β), and to two other neurodegenerative mutations, one in the fly LRRK2 orthologue (dLRRK) the other in eggroll, a model of general neurodegeneration in Drosophila. Stimuli were contrast reversing gratings spanning 64 spatiotemporal frequency combinations. We recorded the steady-state visually-evoked response amplitude across all combinations. We found that the pattern of neuronal responses differed between genotypes. Wild-type and early-onset PD flies formed separate clusters; the late-onset mutation is an outlier. Neuronal responses in early-onset PD flies were stronger than in wild-types. Multivariate pattern analysis grouped flies by PD/non-PD genotype with an accuracy >85%. We propose that machine learning algorithms may be useful in increasing the diagnostic specificity of human electrophysiological measurements in both animal models and PD patients.

Highlights

Parkinson’s disease, first described in 1817 by James Parkinson[1], is a chronic, progressive neurodegenerative disease affecting ~0.2–0.3% of the population, with an increased prevalence of ~1–2% in those aged over 502,3
While Parkinson’s Disease (PD) was once considered to have only a weak genetic component, the discovery of genes associated with PD has revolutionised the study of the disease using genetically tractable model organisms, such as Drosophila[16]
PINK1B9, DJ-1αΔ72 and DJ-1βΔ93 stocks were generously gifted by Dr Alex Whitworth (The University of Sheffield, UK). wDahomey flies were a kind gift from Dr Susan Broughton (The University of Lancaster, UK)[35]

Summary

Introduction

Parkinson’s disease, first described in 1817 by James Parkinson[1], is a chronic, progressive neurodegenerative disease affecting ~0.2–0.3% of the population, with an increased prevalence of ~1–2% in those aged over 502,3. Whilst commonly considered a motor disorder, characterised by postural instability, bradykinesia, rigidity and tremor, a number of visual perturbations have been reported in PD patients[4,5,6] These include, but are not restricted to, hallucinations[7], perturbed visual acuity[8], double vision (Diplopia)[9], dry eyes[10], altered contrast sensitivity[11], and light sensitivity[12]. The superficial surface of the Drosophila eye bears little resemblance to that of vertebrates, the underlying retinal networks show many homologies This was first recognised by Cajal, who pointed out that the fly amacrine cell and medulla intrinsic neurons are homologous to the vertebrate horizontal and amacrine cells, all mediating lateral interactions[23]. Such is the degree of similarity that there is little doubt that both systems have both a common neurogenetic ancestor and that both have been constrained throughout evolutionary history to solve common problems in decoding the environment

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