Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes

Hannah Julienne,Edgar Buhl,David S Leslie,James J.L Hodge

doi:10.1016/j.nbd.2017.04.014

Hannah Julienne, Edgar Buhl + Show 2 more

Open Access

https://doi.org/10.1016/j.nbd.2017.04.014

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Abstract

Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism. We examined memory performance and circadian rhythms in flies with loss-of-function mutations in two PD genes: PINK1 and parkin. We found learning and memory abnormalities in both mutant genotypes, as well as a weakening of circadian rhythms that is underpinned by electrophysiological changes in clock neurons. Our study paves the way for further work that may help us understand the mechanisms underlying these neglected aspects of PD, thus identifying new targets for treatments to address these non-motor problems specifically and perhaps even to halt disease progression in its prodromal phase.

Highlights

Parkinson’s disease (PD) is more commonly associated with its debilitating motor symptoms, which include tremor, rigidity and slowness of movement
PINK1 null flies display a learning impairment, while parkin null flies display a slower rate of memory decay following acquisition
Young flies were used for all experiments presented here: PD is generally a progressive disorder, these particular mutations cause an early-onset form of the disease and non-motor symptoms can be present long before clinical diagnosis

Summary

Introduction

Parkinson’s disease (PD) is more commonly associated with its debilitating motor symptoms, which include tremor, rigidity and slowness of movement. These symptoms have been linked with the degeneration of dopamine (DA) neurons, and treatments for the disease have primarily been developed to treat symptoms by compensating for depleted levels of DA in the brain. It is becoming increasingly clear that PD patients display a wide range of non-motor symptoms that most treatments are not designed to address and may even make worse [1, 2, 3] These include problems related to cognition and disruption of the sleep-wake cycle. Sleep impairments are common, affecting up to two-thirds of PD patients, and include disorders such as insomnia, excessive daytime sleepiness and REM sleep behaviour disorder (RBD) [6, 7, 8]

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