Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

• Published in: Nature neuroscience Vol. 20; no. 11; pp. 1560 - 1568
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017
• Subjects: 101/28; 13; 13/1; 13/51; 42; 42/109; 631/378/1689; 631/45/882; 64; 64/11; 64/60; 82; 82/58; 96; 96/34; alpha-Synuclein - biosynthesis; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedicine; Caenorhabditis elegans; Cells, Cultured; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dopamine - biosynthesis; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Female; Humans; Levodopa - pharmacology; Levodopa - therapeutic use; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurobiology; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurosciences; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4641

Dopamine has long been thought to contribute to neurodegeneration in Parkinson's disease. The authors show that dopamine-induced neuron death in the substantia nigra is dependent on α-synuclein and coincides with increased levels of α-synuclein oligomers. The results suggest a synergistic interaction between dopamine and α-synuclein that underlies neuronal vulnerability in disease. 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.