Dopamine induces soluble alpha-synuclein oligomers and nigrostriatal degeneration

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

来源：Nature Neuroscience, 2017, 20(11): 1560-+.

DOI：10.1038/nn.4641

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 alpha-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in a-synuclein transgenic mice. To address this, we manipulated both dopamine levels and alpha-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 alpha-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic alpha-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of alpha-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 alpha-synuclein aggregation.

• 出版日期2017-11
• 单位西北大学