Assembly of the endocytic machinery is a constitutively active process that is important for the organization of the plasma membrane, signal transduction, and membrane trafficking. Existing research has focused on the stochastic nature of endocytosis. Here, we report the emergence of the collective dynamics of endocytic proteins as periodic traveling waves on the cell surface. Coordinated clathrin assembly provides the earliest spatial cue for cortical waves and sets the direction of propagation. Surprisingly, the onset of clathrin waves, but not individual endocytic events, requires feedback from downstream factors, including FBP17, Cdc42, and N-WASP. In addition to the localized endocytic assembly at the plasma membrane, intracellular clathrin and phosphatidylinositol-3,4-bisphosphate predict the excitability of the plasma membrane and modulate the geometry of traveling waves. Collectively, our data demonstrate the multiplicity of clathrin functions in cortical pattern formation and provide important insights regarding the nucleation and propagation of single-cell patterns.
Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1's 5-phosphatase module in this process is well recognized, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin-coated intermediates, strongly implicating Sac domain's activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson's disease.