Synergistic Effects of Pesticides and Metals on the Fibrillation of α-Synuclein: Implications for Parkinson’s Disease
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:
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.
References (39)
Aluminum-containing antacids as a cause of idiopathic Parkinson’s disease
Med. Hypotheses
(1999)- et al.
Synthetic filaments assembled from C-terminally truncated α-synuclein
FEBS Lett.
(1998) - et al.
Effects of the mutations Ala(30) to Pro and Ala(53) to Thr on the physical and morphological properties of α-synuclein protein implicated in Parkinson’s disease
FEBS Lett.
(1998) - et al.
Conformational properties of α-synuclein in its free and lipid-associated states
J. Mol. Biol.
(2001) - et al.
Discrete intermediates versus molten globule models for protein folding: characterization of partially folded intermediates of apomyoglobin
Fold Des.
(1998) - et al.
Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson’s disease: a LAMMA study
Brain Res.
(1992) - et al.
Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease
Brain Res.
(1998) - et al.
β-Synuclein inhibits α-synuclein aggregation. A possible role as an anti-Parkinsonian factor
Neuron
(2001) - et al.
Epitope mapping of LB509, a monoclonal antibody directed against human α-synuclein
Neurosci. Lett.
(1999) - et al.
The herbicide paraquat causes up-regulation and aggregation of α-synuclein in mice. Paraquat and α-synuclein
J. Biol. Chem.
(2002)
The herbicide paraquat causes up-regulation and aggregation of α-synuclein in mice. Paraquat and α-synuclein
J. Biol. Chem.
Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavin T1
Anal. Biochem.
Both familial Parkinson’s disease mutations accelerate α-synuclein aggregation
J. Biol. Chem.
The role of environmental toxins in the etiology of Parkinson’s disease
Trends Neurosci.
Anion-induced folding of staphylococcal nuclease: characterization of multiple equilibrium partially folded intermediates
J. Mol. Biol.
Stabilization of partially folded conformation during α-synuclein oligomerization in both purified and cytosolic preparations
J. Biol. Chem.
Evidence for a partially folded intermediate in α-synuclein fibril formation
J. Biol. Chem.
Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein. A possible molecular link between Parkinson’s disease and heavy metal exposure
J. Biol. Chem.
Pesticides directly accelerate the rate of α-synuclein fibril formation: a possible factor in Parkinson’s disease
FEBS Lett.
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