Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Abstract

The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome

“…As we show above, αII-spectrin cellular distribution can be disrupted by mutant βII-spectrin to cause these partners to co-aggregate, or otherwise continue to associate in aberrant cellular patterns. Since βII-and αII-spectrin are critically involved in localizing and stabilizing ion channels [1][2][3] , going forward it will be critical to elucidate whether these tightly intertwined partners share pathways disrupted in channelopathies underlying seizures and epilepsy.…”

“…A subcortical network of F-actin-and ankyrin-bound βII-/αII-spectrin tetramers promotes membrane stability and helps organizing membrane proteins within specialized microdomains [1][2][3] . Thus, pathogenic SPTBN1 variants could impair neuronal development and/or function by altering βII-spectrin interaction with F-actin and other cytoskeletal partners or their submembrane availability.…”

“…Some spectrins also enable intracellular organelle transport 3 . Unsurprisingly, deficits in spectrins underlie several neurodevelopmental and neurodegenerative disorders [4][5][6] .…”

“…The spectrin meshwork is formed by heterodimeric units of α- and β-spectrin assembled side-to-side in antiparallel fashion, which then form head-to-head tetramers that crosslink F-actin to form spectrin-actin arrays 1,2 . Mammalian neurons express the most diverse repertoire of spectrins (αII- and βI-V spectrins) of any cell type 3 . Together with ankyrins, spectrins self-assemble with both remarkable long-range regularity and micro- and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins 3 .…”

“…Mammalian neurons express the most diverse repertoire of spectrins (αII- and βI-V spectrins) of any cell type 3 . Together with ankyrins, spectrins self-assemble with both remarkable long-range regularity and micro- and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins 3 . Some spectrins also enable intracellular organelle transport 3 .…”