Mor, Danielle E.Tsika, ElpidaMazzulli, Joseph R.Gould, Neal S.Kim, HannaDaniels, Malcolm J.Doshi, ShacheeGupta, PreetikaGrossman, Jennifer L.Tan, Victor X.Kalb, Robert G.Caldwell, Kim A.Caldwell, Guy A.Wolfe, John H.Ischiropoulos, Harry2017-12-042017-12-042017-12-04201710.1038/nn.4641https://infoscience.epfl.ch/handle/20.500.14299/142612WOS:000413916800017Parkinson'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.text::journal::journal article::research article