Pattern Formation in the Axon: Self-Assembly of the Neuronal Membrane Periodic Skeleton

Neuronal axons are crucial to the connectivity of the nervous system; however, they are vulnerable to damage through injury and neurodegenerative diseases, both of which can disrupt the internal cell cytoskeleton, resulting in cell death or loss of function. Recent advances in super-resolution microscopy techniques have exposed a highly organised cytoskeletal structure within the axon, referred to as the membrane-associated periodic skeleton (MPS). This structure consists of rings of actin filaments, spaced periodically at approximately 190 nm intervals, and connected laterally by spectrin tetramers. The mechanism by which this structure forms, and the benefits derived from its organisation, are currently unknown. We use in silico models to investigate the factors driving self-assembly of the MPS structure in axons. We model key cytoskeletal components, actin and spectrin, simulating their motion within an axon-like environment. We include stochastic protein-level events to model relevant biological processes, such as the formation and turnover of crosslinks, and polymerisation of actin filaments. We seek evidence of actin ring formation and periodic patterning through analysis of configurational data. Through searching parameter space, we show that self-assembly of an MPS-like structure is possible under specific parameter values, with polymerisation of actin within the cell environment, and its interactions with dense populations of membrane-associated spectrin, playing a key role in overall patterning.