Dopamine induces soluble alpha-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 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.

Description
Keywords
SUBSTANTIA-NIGRA NEURONS, PARKINSONS-DISEASE, CAENORHABDITIS-ELEGANS, OXIDATIVE DAMAGE, LEWY BODIES, IN-VIVO, NEURODEGENERATION, MICE, MUTATION, PROTEIN, Neurosciences
Citation
Mor, D. E., Tsika, E., Mazzulli, J. R., Gould, N. S., Kim, H., Daniels, M. J., Doshi, S., Gupta, P., Grossman, J. L., Tan, V. X., Kalb, R. G., Caldwell, K. A., Caldwell, G. A., Wolfe, J. H., & Ischiropoulos, H. (2017). Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. In Nature Neuroscience (Vol. 20, Issue 11, pp. 1560–1568). Springer Science and Business Media LLC. https://doi.org/10.1038/nn.4641