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Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line.

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Author

  • Julie Lotharius
  • Sebastian Barg
  • Pia Wiekop
  • Cecilia Lundberg
  • Heather K. Raymon
  • Patrik Brundin

Summary, in English

Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinsons disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-synuclein is a presynaptic nerve terminal protein of unknown function, though some studies suggest it is important for synapse formation and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in downregulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Since extra-vesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinsons disease by triggering protracted, low-grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.

Department/s

Publishing year

2002

Language

English

Pages

38884-38894

Publication/Series

Journal of Biological Chemistry

Volume

277

Issue

41

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Islet cell physiology

ISBN/ISSN/Other

  • ISSN: 1083-351X