Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

Danielle E. Mor, Elpida Tsika, Joseph R. Mazzulli, Neal S. Gould, Hanna Kim, Malcolm J. Daniels, Shachee Doshi, Preetika Gupta, Jennifer L. Grossman, Victor X. Tan, Robert G. Kalb, Kim A. Caldwell, Guy A. Caldwell, John H. Wolfe, Harry Ischiropoulos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1560-1568
Number of pages9
JournalNature neuroscience
Issue number11
StatePublished - 2017

ASJC Scopus subject areas

  • General Neuroscience


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