Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.
Danielle E MorElpida TsikaJoseph R MazzulliNeal S GouldHanna KimMalcolm J DanielsShachee DoshiPreetika GuptaJennifer L GrossmanVictor X TanRobert G KalbKim A CaldwellGuy A CaldwellJohn H WolfeHarry IschiropoulosPublished in: Nature neuroscience (2017)
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.
Keyphrases
- uric acid
- cell death
- poor prognosis
- prefrontal cortex
- wild type
- endothelial cells
- metabolic syndrome
- spinal cord
- diabetic rats
- high glucose
- computed tomography
- magnetic resonance imaging
- high fat diet induced
- binding protein
- drug delivery
- climate change
- adipose tissue
- machine learning
- long non coding rna
- electronic health record
- artificial intelligence
- deep learning