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

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.

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…A further potential connection with regards to the above is pesticides' potential suppression of the Wnt/β-catenin signaling pathway [106][107][108]. Paraquat exposure altered the levels of the Wnt pathway genes in mouse neural progenitor cells [106], rotenone impaired Wnt signaling in a Drosophila PD model [107] and Deltamethrin also reduced Wnt signaling pathway genes in zebrafish's development of swim bladder [108]. Wnt signaling is known to be impaired in AD [109][110][111], and activation of the Wnt/β-catenin signaling pathway represses BACE-1 expression [112].…”

Drosophila Models of Sporadic Parkinson’s Disease

“…A recent study by Stephano et al [ 71 ] showed that chronic exposure to 500 µM rotenone does not cause a significant DA neuron loss for at least up to 10 days, whereas the climbing ability declines from day 6 onwards. They took advantage of the absence of neuronal loss and isolated DA neurons after 3 days of rotenone treatment, the timepoint considered to be the presymptomatic phase, and analyzed their transcriptome.…”

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

“…We found evidence for shared functional processes and pathways among DEGs in these two models. Among upregulated genes, strong enrichment occurred in biological processes related to Wnt signaling pathway, transcription regulation, cilia functions, and estradiol responses, all of which have previously been shown to be associated with PD dysfunctions (Gonzalez-Reyes et al, 2012;Siani et al, 2017;Stephano et al, 2018). For example, impaired Wnt signaling in DAergic neurons has been associated with pathogenesis in a rotenone-triggered PD model (Stephano et al, 2018).…”

“…Among upregulated genes, strong enrichment occurred in biological processes related to Wnt signaling pathway, transcription regulation, cilia functions, and estradiol responses, all of which have previously been shown to be associated with PD dysfunctions (Gonzalez-Reyes et al, 2012;Siani et al, 2017;Stephano et al, 2018). For example, impaired Wnt signaling in DAergic neurons has been associated with pathogenesis in a rotenone-triggered PD model (Stephano et al, 2018). Loss of cilia will decrease the ability of cholinergic neurons to respond to a sonic hedgehog signal that triggers neuroprotective signaling toward DAergic circuits (Gonzalez-Reyes et al, 2012).…”