Impaired Wnt signaling in dopamine containing neurons is associated with pathogenesis in a rotenone triggered Drosophila Parkinson\u2019s disease model

Flora Stephano,Thomas Roeder,Julia Hoffmann,Iris Bruchhaus,Christine Fink,Stella Nolte,Samar El-Kholy,Jakob Von Frieling

doi:10.1038/s41598-018-20836-w

Abstract

Parkinson’s disease, which is the one of the most common neurodegenerative movement disorder, is characterized by a progressive loss of dopamine containing neurons. The mechanisms underlying disease initiation and development are not well understood and causative therapies are currently not available. To elucidate the molecular processes during early stages of Parkinson’s disease, we utilized a Drosophila model. To induce Parkinson’s disease-like phenotypes, we treated flies with the pesticide rotenone and isolated dopamine producing neurons of animals that were at an early disease stage. Transcriptomic analyses revealed that gene ontologies associated with regulation of cell death and neuronal functions were significantly enriched. Moreover, the activities of the MAPK/EGFR- and TGF-β signaling pathways were enhanced, while the Wnt pathway was dampened. In order to evaluate the role of Wnt signaling for survival of dopaminergic neurons in the disease model, we rescued the reduced Wnt signaling activity by ectopic overexpression of armadillo/β-catenin. This intervention rescued the rotenone induced movement impairments in the Drosophila model. Taken together, this initial study showed a highly relevant role of Wnt signaling for dopamine producing neurons during pathogenesis in Parkinson’s disease and it implies that interfering with this pathway might by a suitable therapeutic option for the future.

Highlights

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder with an incidence of about 1% in people older than 65 years[1,2]
Previous studies have shown that detectable motor impairments and DA neuron loss start after chronic exposure with rotenone for several days and that this symptomatic phase starts after the majority of DA neurons were already severely damaged[20,23]
In order to reach this ambitious goal, focusing exclusively on these dopamine producing cells being in an early stage was mandatory

Summary

Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder with an incidence of about 1% in people older than 65 years[1,2]. An association between early stages of the disease and impaired Wnt signaling has been shown in PD8,13,14, it is not generally accepted that deregulated Wnt signaling is a driving force underlying PD development. To study these early molecular events in DA neurons that lead to PD, animal models have been the foremost tools. Amongst these affected systems are the Wnt-, MAPK/EGFR-, TGF-β-, and TOR-signaling pathways, which are known to be important for cell survival and/or cell death in the CNS

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