Abstract
Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease
We found pathways previously implicated in human PD such as such as axonal guidance signaling [17,37], pathways linked to other neurodegenerative diseases such as Wnt/ b catenin signaling [38], in addition to pathways not previously associated with PD such as basal cell carcinoma, role of osteoblasts, osteoclasts and chondrocytes in rheumatoid arthritis, human embryonic stem cell pluripotency, role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis
Administration of pesticides produced the neuropathological features of PD, in that they produced loss of nigrostriatal DA neurons and increased a-synuclein immunoreactivity, which is a protein found in lewy bodies, and is the most characteristic feature of idiopathic PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease. It is characterized by tremor, rigidity, slowness of voluntary movement and postural instability. The motor symptoms of PD result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Intracytoplasmic eosinophilic inclusions composed of a-synuclein, are found in lewy bodies in the remaining, intact nigral neurons [1]. As the etiology of the majority of human PD cases is unknown, several neurotoxicant models of PD have been developed to correctly model PD [4,5]. Evidence for an environmental basis of PD comes from epidemiological studies and experimental animals exposed to environmental toxins [6] suggesting an important role of pesticides. Pesticides are defined as any substance or mixture intended for preventing, destroying, repelling or mitigating pests
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