Effect of metals on herbicides–α‐synuclein association: A possible factor in neurodegenerative disease studied by capillary electrophoresis

Abstract

The aggregation of alpha-synuclein in the dopaminergic neurons of the substantia nigra is a critical step in the Parkinson's disease (PD). The etiology of the disease is unknown but recent epidemiological and experimental studies have renewed interest in the hypothesis that environmental factors, especially herbicides and metals, have a role on the pathogenesis of PD. For the first time, the association constants of alpha-synuclein with five herbicides have been calculated using a capillary electrophoresis (CE) method. In addition, the effect of a number of metals on this binding has been investigated. It appears that the herbicides preferentially bind to a partially folded intermediate conformation of alpha-synuclein induced by manganese, aluminium, cadmium, copper and zinc. Then, metal increases the synuclein-herbicide association. However, this study shows contrasting actions with the antibiotic rifampicin and magnesium addition leading to a decrease of the alpha-synuclein-herbicide interaction even if other metals are present in the bulk solvent. Considering epidemiological studies, all these results suggest an underlying molecular basis for PD and related body diseases.

Structural basis behind the interaction of Zn2+ with the protein α-synuclein and the Aβ peptide: A comparative analysis

“…The simplest mechanism proposed involves a direct effect of the metal ions on the aggregation of the target proteins linked to these diseases. The effects reported for Zn 2+ ions on AS fibrillation revealed that metal concentrations in the mM range, far greater than those normally occurring in tissues, are necessary to accelerate the amyloid aggregation of the protein [67,68,[72][73][74][75], which argue against the physiological relevance that these effects might have on the etiology of the disease. Furthermore, no structural characterization of the Zn 2+ binding sites, or the identification of the amino acids involved in the metal-AS interactions has been reported to date.…”

“…Interestingly, despite of the reported evidences that link Zn 2+ with the pathophysiology of PD and the fact that this metal ion was shown to promote AS fibrillation in vitro [67,68,[72][73][74][75], neither the structural characterization of the binding sites nor the identification of the amino acids involved in the interaction of Zn 2+ with the protein AS have been carried out. Accordingly, in this work we sought to delineate the structural basis behind the interaction of Zn 2+ with AS, as a first step towards the understanding of the molecular mechanism by which Zn 2+ accelerates AS filament assembly.…”

Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

“…Most cases of sporadic PD are considered to be idiopathic, but it is generally believed that the disease is a result of unknown environmental factors [49]. Recent evidence has suggested that some of these cases may be related to the exposure to environmental factors including heavy metals and pesticides [50,51]. Exposure to such factors could have significant effects on a-Syn regulation by both barriers and possibly contribute to PD pathology.…”

Biophysical Characterization of α-Synuclein and Rotenone Interaction

“…Do pesticides remain bound to α-synuclein once misfolding and fibrillation is triggered? Biophysical studies are essential to address these questions [85,86,87,88,89]. …”