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Dysregulated dopamine storage increases the vulnerability to alpha-synuclein in nigral neurons

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Author

Summary, in English

Impairments in the capacity of dopaminergic neurons to handle cytoplasmic dopamine may be a critical factor underlying the selective vulnerability of midbrain dopamine neurons in Parkinson's disease. Furthermore, toxicity of alpha-synuclein in dopaminergic neurons has been suggested to be mediated by direct interaction between dopamine and alpha-synuclein through formation of abnormal alpha-synuclein species, although direct in vivo evidence to support this hypothesis is lacking. Here, we investigated the role of dopamine availability on alpha-synuclein mediated neurodegeneration in vivo. We found that overexpression of alpha-synuclein in nigral dopamine neurons in mice with deficient vesicular storage of dopamine led to a significant increase in dopaminergic neurodegeneration. Importantly, silencing the tyrosine hydroxylase enzyme - thereby reducing dopamine content in the nigral neurons - reversed the increased vulnerability back to the baseline level observed in wild-type littermates, but failed to eliminate it completely. Importantly, TH knockdown was not effective in altering the toxicity in the wild-type animals. Taken together, our data suggest that under normal circumstances, in healthy dopamine neurons, cytoplasmic dopamine is tightly controlled such that it does not contribute significantly to alpha-synuclein mediated toxicity. Dysregulation of the dopamine machinery in the substantia nigra, on the other hand, could act as a trigger for induction of increased toxicity in these neurons and could explain how these neurons become more vulnerable and die in the disease process. (C) 2012 Elsevier Inc. All rights reserved.

Publishing year

2012

Language

English

Pages

367-377

Publication/Series

Neurobiology of Disease

Volume

47

Issue

3

Document type

Journal article

Publisher

Elsevier

Topic

  • Neurosciences

Keywords

  • Short hairpin RNA
  • Tyrosine hydroxylase
  • Adeno-associated virus
  • VMAT2
  • Transgenic mice

Status

Published

Research group

  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 0969-9961