Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

Nat Neurosci. 2017 Nov;20(11):1560-1568. doi: 10.1038/nn.4641. Epub 2017 Sep 18.

Abstract

Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Cells, Cultured
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dopamine / biosynthesis*
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Female
  • Humans
  • Levodopa / pharmacology
  • Levodopa / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology
  • alpha-Synuclein / biosynthesis*

Substances

  • SNCA protein, human
  • alpha-Synuclein
  • Levodopa
  • Dopamine