The presence of aggregated alpha-synuclein molecules is a common denominator in a variety of neurodegenerative disorders. Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (Syk), which phosphorylates three tyrosyl residues in its C-terminal domain (Y-125, Y-133, and Y-136), as revealed from experiments with mutants where these residues have been individually or multiply replaced by phenylalanine. In contrast, only Y-125 is phosphorylated by Lyn and c-Fgr. Eosin-induced multimerization is observed with wild-type alpha-syn, either phosphorylated or not by Lyn, and with all its Tyr to Phe mutants but not with the protein previously phosphorylated by Syk. Syk-mediated phosphorylation also counteracts alpha-syn assembly into filaments as judged from the disappearance of alpha-syn precipitated upon centrifugation at 100,000 x g. We also show that Syk and alpha-syn colocalize in the brain, and upon cotransfection in Chinese hamster ovary cells, alpha-syn becomes Tyr-phosphorylated by Syk. Moreover, Syk and alpha-syn interact with each other as judged from the mammalian two-hybrid system approach. These data suggest that Syk or tyrosine kinase(s) with similar specificity may play an antineurodegenerative role by phosphorylating a-syn, thereby preventing its aggregation.