alpha -Synuclein (alpha -Syn) is implicated in the pathogenesis of Parkinso
n's Disease, genetically through missense mutations linked to early onset d
isease and pathologically through its presence in Lewy bodies. alpha -Syn i
s phosphorylated on serine residues; however, tyrosine phosphorylation of a
lpha -Syn has not been established (1, 2). A comparison of the protein sequ
ence between Synuclein family members revealed that all four tyrosine resid
ues of alpha -Syn are conserved in all orthologs and beta -Syn paralogs des
cribed to date, suggesting that these residues may be of functional importa
nce (3). For this reason, experiments were performed to determine whether a
lpha -Syn could be phosphorylated on tyrosine residue(s) in human cells. In
deed, alpha -Syn is phosphorylated within 2 min of pervanadate treatment in
alpha -Syn-transfected cells. Tyrosine phosphorylation occurs primarily on
tyrosine 125 and was inhibited by PP2, a selective inhibitor of Src protei
n-tyrosine kinase (PTK) family members at concentrations consistent with in
hibition of Src function (4). Finally, we demonstrate that alpha -Syn can b
e phosphorylated directly both in cotransfection experiments using c-Src an
d Fyn expression vectors and in in vitro kinase assays with purified kinase
s. These data suggest that alpha -Syn can be a target for phosphorylation b
y the Src family of PTKs.