Synapsin E-domain is essential for a-synuclein function

The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here we identify the synapsin E-domain as an essential functional binding-partner of a-synuclein (a-syn). Synapsin E-domain allows a-syn functionality, binds to a-syn, and is necessary and sufficient for enabling effects of a-syn at the synapse. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.