Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

Danielle E. Mor, Elpida Tsika, Joseph R. Mazzulli, Neal S. Gould, Hanna Kim, Malcolm J. Daniels, Shachee Doshi, Preetika Gupta, Jennifer L. Grossman, Victor X. Tan, Robert G. Kalb, Kim A. Caldwell, Guy A. Caldwell, John H. Wolfe, Harry Ischiropoulos*

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1560-1568
Number of pages9
JournalNature Neuroscience
Volume20
Issue number11
DOIs
StatePublished - Jan 1 2017

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Synucleins
Dopamine
Dopaminergic Neurons
Parkinson Disease
Cell Death
Lewy Bodies
Poisons
Caenorhabditis elegans
Tyrosine 3-Monooxygenase
Substantia Nigra
Locomotion
Transgenic Mice
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mor, D. E., Tsika, E., Mazzulli, J. R., Gould, N. S., Kim, H., Daniels, M. J., ... Ischiropoulos, H. (2017). Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. Nature Neuroscience, 20(11), 1560-1568. https://doi.org/10.1038/nn.4641
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. / Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. In: Nature Neuroscience. 2017 ; Vol. 20, No. 11. pp. 1560-1568.
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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.",
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Mor, DE, Tsika, E, Mazzulli, JR, Gould, NS, Kim, H, Daniels, MJ, Doshi, S, Gupta, P, Grossman, JL, Tan, VX, Kalb, RG, Caldwell, KA, Caldwell, GA, Wolfe, JH & Ischiropoulos, H 2017, 'Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration', Nature Neuroscience, vol. 20, no. 11, pp. 1560-1568. https://doi.org/10.1038/nn.4641

Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. / 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.

In: Nature Neuroscience, Vol. 20, No. 11, 01.01.2017, p. 1560-1568.

Research output: Contribution to journalArticle

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AU - Mazzulli, Joseph R.

AU - Gould, Neal S.

AU - Kim, Hanna

AU - Daniels, Malcolm J.

AU - Doshi, Shachee

AU - Gupta, Preetika

AU - Grossman, Jennifer L.

AU - Tan, Victor X.

AU - Kalb, Robert G.

AU - Caldwell, Kim A.

AU - Caldwell, Guy A.

AU - Wolfe, John H.

AU - Ischiropoulos, Harry

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N2 - 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.

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