Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration
Nature neuroscience, 2017•nature.com
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 …
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 …
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.
nature.com