Dopamine induces soluble ?-synuclein oligomers and nigrostriatal degeneration.

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

SUBMITTER: Mor DE 

PROVIDER: S-EPMC5893155 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature