Interactions among α-synuclein, dopamine, and biomembranes: Some clues for understanding neurodegeneration in Parkinson's disease

Jean Christophe Rochet, Tiago Fleming Outeiro, Kelly A. Conway, Tomas T. Ding, Michael J. Volles, Hilal A. Lashuel, Robert M. Bieganski, Susan L. Lindquist, Peter J. Lansbury

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Abstract

Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein α-synuclein plays a role in the pathogenesis of PD: Fibrillar α-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in α-synuclein are linked to early-onset disease. Accordingly, the fibrillization of α-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the α-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar α-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. α-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with α-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic α-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of α-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of α-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random α-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by α-synuclein is necessary for neurodegeneration in transgenic animal models of PD.

Original languageEnglish
Pages (from-to)23-33
Number of pages11
JournalJournal of Molecular Neuroscience
Volume23
Issue number1-2
Publication statusPublished - 1 Apr 2004
Externally publishedYes

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Keywords

  • Dopamine
  • Fibril
  • Membrane
  • Parkinson's disease
  • Protofibril
  • Synuclein
  • Yeast

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry
  • Genetics

Cite this

Rochet, J. C., Outeiro, T. F., Conway, K. A., Ding, T. T., Volles, M. J., Lashuel, H. A., Bieganski, R. M., Lindquist, S. L., & Lansbury, P. J. (2004). Interactions among α-synuclein, dopamine, and biomembranes: Some clues for understanding neurodegeneration in Parkinson's disease. Journal of Molecular Neuroscience, 23(1-2), 23-33.