Synapsin E-domain is essential for [alpha]-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 [alpha]-synuclein ([alpha]-syn). Synapsin E-domain allows [alpha]-syn functionality, binds to [alpha]-syn, and is necessary and sufficient for enabling effects of [alpha]-syn at synapses of cultured mouse hippocampal neurons. 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.