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The Journal of Neuroscience, August 15, 2000, 20(16):6048-6054
The A53T  -Synuclein Mutation Increases Iron-Dependent
Aggregation and Toxicity
Natalie
Ostrerova-Golts1,
Leonard
Petrucelli1,
John
Hardy3,
John M.
Lee1, 2,
Matthew
Farer3, and
Benjamin
Wolozin1
Departments of 1 Pharmacology and
2 Pathology, Loyola University Medical Center, Maywood,
Illinois 60153, and 3 Department of Pharmacology, Mayo
Clinic, Jacksonville, Florida 32224
Parkinson's disease (PD) is the most common motor disorder
affecting the elderly. PD is characterized by the formation of Lewy
bodies and death of dopaminergic neurons. The mechanisms underlying PD
are unknown, but the discoveries that mutations in  -synuclein can
cause familial PD and that -synuclein accumulates in Lewy bodies
suggest that -synuclein participates in the pathophysiology of PD.
Using human BE-M17 neuroblastoma cells overexpressing wild-type, A53T,
or A30P -synuclein, we now show that iron and free radical generators, such as dopamine or hydrogen peroxide, stimulate the production of intracellular aggregates that contain -synuclein and
ubiquitin. The aggregates can be identified by immunocytochemistry, electron microscopy, or the histochemical stain thioflavine S. The amount of aggregation occurring in the cells is dependent on the
amount of -synuclein expressed and the type of -synuclein expressed, with the amount of -synuclein aggregation following a
rank order of A53T > A30P > wild-type > untransfected. In addition to stimulating aggregate formation,
-synuclein also appears to induce toxicity. BE-M17 neuroblastoma
cells overexpressing -synuclein show up to a fourfold increase in
vulnerability to toxicity induced by iron. The vulnerability follows
the same rank order as for aggregation. These data raise the
possibility that -synuclein acts in concert with iron and dopamine
to induce formation of Lewy body pathology in PD and cell death in PD.
Key words:
Parkinson's disease; Lewy body; oxidation; neurodegeneration; ubiquitin; dopamine
Copyright © 2000 Society for Neuroscience 0270-6474/00/20166048-07$05.00/0
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