Alpha-synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells.
Alpha-synuclein is a presynaptic protein strongly implicated in Parkinson's disease (PD). Because dopamine neurons are invariably compromised during pathogenesis in PD, we have been exploring the functions of alpha-synuclein with particular relevance to dopaminergic neuronal cells. We previously discovered reduced tyrosine hydroxylase (TH) activity and minimal dopamine synthesis in stably-transfected MN9D cells overexpressing either wild-type or A53T mutant (alanine to threonine at amino acid 53) alpha-synuclein. TH, the rate-limiting enzyme in dopamine synthesis, converts tyrosine to l-dihydroxyphenylalanine (L-DOPA), which is then converted to dopamine by the enzyme, aromatic amino acid decarboxylase (AADC). We confirmed an interaction between alpha-synuclein and AADC in striatum. We then sought to determine whether wild-type or A53T mutant alpha-synuclein might have affected AADC activity in dopaminergic cells. Using HPLC with electrochemical detection, we measured dopamine and related catechols after L-DOPA treatments to bypass the TH step. We discovered that while alpha-synuclein did not reduce AADC protein levels, it significantly reduced AADC activity and phosphorylation in our cells. These novel findings further support a role for alpha-synuclein in dopamine homeostasis and may explain, at least in part, the selective vulnerability of dopamine neurons that occurs in PD.
Tehranian
Roya
R
Department of Neurology, University of Pittsburgh, School of Medicine, Pitttsburgh, Pennsylvania 15213, USA.
Montoya
Susana E
SE
Van Laar
Amber D
AD
Hastings
Teresa G
TG
Perez
Ruth G
RG
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000096:biosynthesis*; D025461:Feedback, Physiological / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology; D010766:Phosphorylation; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D051844:alpha-Synuclein; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine