Elsevier

NeuroToxicology

Volume 23, Issues 4–5, October 2002, Pages 527-536
NeuroToxicology

Synergistic Effects of Pesticides and Metals on the Fibrillation of α-Synuclein: Implications for Parkinson’s Disease

https://doi.org/10.1016/S0161-813X(02)00067-0Get rights and content

Abstract

Aggregation of α-synuclein has been implicated in the formation of proteinaceous inclusions in the brain (Lewy bodies, Lewy neurites) that are characteristic of neurodegenerative diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLBs). The etiology of PD is unknown, but recent work has shown that except in rare cases, there appears to be no direct genetic basis. However, several studies have implicated environmental factors, especially pesticides and metals. Here we show that certain pesticides and metals induce a conformational change in α-synuclein and directly accelerate the rate of formation of α-synuclein fibrils in vitro. In addition, the simultaneous presence of metal and pesticide led to synergistic effects on the rate of fibrillation. We propose a model in which environmental factors in conjunction with genetic susceptibility may form the underlying molecular basis for idiopathic PD.

Section snippets

INTRODUCTION

The aggregation of α-synuclein has been implicated in the formation of inclusions in the brain, Lewy bodies and Lewy neurites, that are characteristic of neurodegenerative diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLBs), as well as intraglial inclusions in multiple system atrophy (MSA) (Spillantini et al., 1998, Iwatsubo et al., 1996, Goedert, 2001). PD is the second most common neurodegenerative disease, affecting an estimated five million people worldwide. Lewy

Materials

α-Synuclein was expressed and purified as described previously (Uversky et al., 2001b). Solutions of metal chlorides and pesticides (dissolved in acetone if necessary) were made by dissolving in pH 7.5 PBS buffer. For aluminum chloride, the initial solution was made at low pH in sodium acetate buffer and adjusted to pH 7.5 with NaOH.

Fibril Formation

Solutions of 71 μM α-synuclein at pH 7.5 in 25 mM Tris, 100 mM NaCl buffer were stirred or shaken at 37 °C. Fibril formation was monitored with thioflavin T (TFT)

RESULTS

We have recently shown that the fibrillation of α-synuclein involves formation of a critical partially folded intermediate species (Uversky et al., 2001b), and that the minimum kinetic scheme for fibrillation is as follows:MonomerIntermediateNucleusFibrils

It is likely that there may be additional oligomeric intermediates on the pathway, as well (Conway et al., 2000). There are a number of factors that accelerate the rate of α-synuclein aggregation and fibril formation: these include

DISCUSSION

Parkinsonism has been associated with long term occupational exposure to pesticides and certain metals. Currently, about one billion pound of pesticides used annually in the US, specific pesticides that have been implicated include: paraquat, organochlorine compounds, dieldrin, 1,1′-(2,2-dichloroethenyldiene)-bis(4-chlorobenzene), hexachlorocyclohexane (lindane). There are many possible mechanisms whereby pesticides and metals could lead to α-synuclein aggregation. Oxidative damage, especially

Acknowledgements

We thank Drs. J. Gillespie, J.W, Langston and D. Di Monte for valuable discussions. This research was supported by grant RO1 NS39985 from the National Institutes of Health.

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