Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

Academic Article

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.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Mor DE; Tsika E; Mazzulli JR; Gould NS; Kim H; Daniels MJ; Doshi S; Gupta P; Grossman JL; Tan VX
  • Start Page

  • 1560
  • End Page

  • 1568
  • Volume

  • 20
  • Issue

  • 11