RGD Reference Report - A role for alpha-synuclein in the regulation of dopamine biosynthesis. - Rat Genome Database

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A role for alpha-synuclein in the regulation of dopamine biosynthesis.

Authors: Perez, RG  Waymire, JC  Lin, E  Liu, JJ  Guo, F  Zigmond, MJ 
Citation: Perez RG, etal., J Neurosci. 2002 Apr 15;22(8):3090-9.
RGD ID: 5129111
Pubmed: PMID:11943812   (View Abstract at PubMed)
PMCID: PMC6757524   (View Article at PubMed Central)
DOI: DOI:20026307   (Journal Full-text)

The alpha-synuclein gene is implicated in the pathogenesis of Parkinson's disease. Although alpha-synuclein function is uncertain, the protein has homology to the chaperone molecule 14-3-3. In addition, alpha-synuclein can bind to 14-3-3, and both alpha-synuclein and 14-3-3 bind to many of the same proteins. Because 14-3-3 binds to and activates tyrosine hydroxylase, the rate-limiting enzyme in dopamine (DA) biosynthesis, we explored whether alpha-synuclein also bound to tyrosine hydroxylase and influenced its activity. Immunoprecipitation revealed an interaction between alpha-synuclein and tyrosine hydroxylase in brain homogenates and MN9D dopaminergic cells. Colocalization of alpha-synuclein with tyrosine hydroxylase was confirmed by immunoelectron microscopy. To explore the consequences of the interaction, we measured the effect of recombinant alpha-synuclein on tyrosine hydroxylase activity in a cell-free system and observed a dose-dependent inhibition of tyrosine hydroxylase by alpha-synuclein. To measure the impact of alpha-synuclein on tyrosine hydroxylase in dopaminergic cells, we stably transfected MN9D cells with wild-type or A53T mutant alpha-synuclein. Overexpression of wild-type or A53T mutant alpha-synuclein did not significantly alter tyrosine hydroxylase protein levels in our stably transfected cells. However, overexpressing cell lines had significantly reduced tyrosine hydroxylase activity and a corresponding reduction in dopamine synthesis. The reduction in cellular dopamine levels was not caused by increased dopamine catabolism or dopamine efflux. These data suggest that alpha-synuclein plays a role in the regulation of dopamine biosynthesis, acting to reduce the activity of tyrosine hydroxylase. If so, a loss of soluble alpha-synuclein, by reduced expression or aggregation, could increase dopamine synthesis with an accompanying increase in reactive dopamine metabolites.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ThRatdopamine biosynthetic process from tyrosine involved_inIMP PMID:11943812BHF-UCL 
SncaRatnegative regulation of dopamine metabolic process involved_inIMP PMID:11943812BHF-UCL 
SncaRatnegative regulation of protein phosphorylation involved_inIMP PMID:11943812BHF-UCL 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SncaRatcytoplasmic vesicle membrane located_inIDA PMID:11943812BHF-UCL 
ThRatcytoplasmic vesicle membrane located_inIDA PMID:11943812BHF-UCL 
SncaRatmitochondrion located_inIDA PMID:11943812BHF-UCL 
ThRatmitochondrion located_inIDA PMID:11943812BHF-UCL 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SncaRatenzyme binding  IPITh (Rattus norvegicus) RGD 
ThRatprotein binding  IPISnca (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Snca  (synuclein alpha)
Th  (tyrosine hydroxylase)


Additional Information