2nd Edition of Pharma R&D and Drug Discovery World Conference 2026

Abstract

The neuronal membrane-associated periodic skeleton (MPS), composed of actin, spectrin, and associated molecules, forms a lattice-like cortical structure whose molecular composition and functions have remained incompletely understood. Using co-immunoprecipitation and mass spectrometry, we identified hundreds of candidate MPS-interacting proteins spanning diverse functional categories. Super-resolution imaging of representative proteins, including previously unknown structural components, motor proteins, cell adhesion molecules (CAMs), ion channels, and signaling proteins, revealed periodic distributions characteristic of the MPS along neurites. Genetic perturbations of the MPS and its interacting proteins indicate roles in axon-axon and axon-dendrite interactions, axon diameter regulation. Functionally, the MPS serves as a dynamic platform for signal integration. It recruits G protein-coupled receptors (GPCRs), CAMs, and receptor tyrosine kinases (RTKs) in response to extracellular cues, promoting colocalization and RTK transactivation that trigger extracellular signal-regulated kinase (ERK) signaling. In addition to signaling, the MPS spatially gates major forms of endocytosis by restricting pit formation to MPS-free “clearing” zones across axonal and somatodendritic compartments. Disruption of the MPS enhances both basal and ligand-induced endocytosis, while ligand-triggered endocytosis activates ERK signaling to further remodel the MPS, establishing a self-reinforcing feedback circuit. Notably, MPS integrity limits amyloid precursor protein (APP) endocytosis and suppresses amyloid-β 1-42 production, linking cytoskeletal organization to neuronal health and disease susceptibility. Together, these findings reveal the MPS as a dynamic, multifunctional scaffold that coordinates structural integrity, protein interactions, receptor signaling, and membrane trafficking, establishing a unifying principle by which cytoskeletal architecture shapes neuronal function, connectivity, and homeostasis.