Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.

Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane-associated periodic skeleton (MPS), an actin spectrin-based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways-CME, caveolin-, flotillin-, and fast endophilin-mediated endocytosis-are spatially gated by the MPS and occur exclusively within MPS-free "clearing" zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular signal-regulated kinase signaling, promoting protease-mediated spectrin cleavage and MPS disruption, which in turn facilitates further endocytosis. Furthermore, the MPS limits amyloid precursor protein endocytosis, thereby suppressing Aβ42 production and linking MPS integrity to neurodegeneration. Our findings establish the MPS as a dynamic, signal-responsive modulator coupling membrane trafficking with cortical cytoskeletal organization and neuronal health.