Towards improved screening of toxins for Parkinson’s risk

Abstract

Parkinson’s disease (PD) is a chronic, progressive and disabling neurodegenerative disorder. The prevalence of PD has risen considerably over the past decades. A growing body of evidence suggest that exposure to environmental toxins, including pesticides, solvents and heavy metals (collectively called toxins), is at least in part responsible for this rapid growth. It is worrying that the current screening procedures being applied internationally to test for possible neurotoxicity of specific compounds offer inadequate insights into the risk of developing PD in humans. Improved screening procedures are therefore urgently needed. Our review first substantiates current evidence on the relation between exposure to environmental toxins and the risk of developing PD. We subsequently propose to replace the current standard toxin screening by a well-controlled multi-tier toxin screening involving the following steps: in silico studies (tier 1) followed by in vitro tests (tier 2), aiming to prioritize agents with human relevant routes of exposure. More in depth studies can be undertaken in tier 3, with whole-organism (in)vertebrate models. Tier 4 has a dedicated focus on cell loss in the substantia nigra and on the presumed mechanisms of neurotoxicity in rodent models, which are required to confirm or refute the possible neurotoxicity of any individual compound. This improved screening procedure should not only evaluate new pesticides that seek access to the market, but also critically assess all pesticides that are being used today, acknowledging that none of these has ever been proven to be safe from a perspective of PD. Importantly, the improved screening procedures should not just assess the neurotoxic risk of isolated compounds, but should also specifically look at the cumulative risk conveyed by exposure to commonly used combinations of pesticides (cocktails). The worldwide implementation of such an improved screening procedure, would be an essential step for policy makers and governments to recognize PD-related environmental risk factors.

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

“…There are many researchers who consider that environmental exposure plays an important role in the degenerative process of the nigrostriatal system that induces the loss of neuromelanin-containing dopaminergic neurons. Others think that exposure to heavy metals, solvents, pesticides, and environmental toxins could be partly responsible for the rapid growth in Parkinson’s disease [ 16 ]. A study on the possible role of exposure to local traffic-related air pollution in central California, USA, which included 761 patients with Parkinson’s disease and 910 healthy controls, concluded that exposure to local traffic-related air pollution is associated with an increased risks of developing Parkinson’s disease [ 17 ].…”

Alpha Synuclein Toxicity and Non-motor Parkinson’s

“…A bidirectional relationship between oxidative/nitrosative stress and aSyn toxicity exists [68]. High levels of reactive oxidative species (ROS) within the neurons have been suggested to induce aSyn toxicity [69][70][71]. Excessive OS, cause peroxidation of the membrane lipids followed by the production of the highly toxic 4-hydroxy-2-nonenal.…”

“…Mitochondrial dysfunction plays a central role in the pathogenesis of PD [81]. Several neurotoxins have been found to provoke high levels of ROS, complex I inhibition and neuronal damage [70] . Additionally, abnormal levels or misfolded forms of aSyn can disrupt the balance of mitochondrial fission and fusion and transport, leading to fragmentate or aggregate mitochondria, impairment of mitochondrial trafficking, electron transport chain, and calcium signaling [81,82].…”