Neurofilaments are the building blocks of the major cytoskeletal network found in the axons of vertebrate neurons. The filaments consist of three distinct molecular-weight subunits—neurofilament-low, neurofilament-medium, and neurofilament-high—which coassemble into 10-nm flexible rods with protruding intrinsically disordered C-terminal sidearms that mediate interfilament interactions and hydrogel formation. Molecular neuroscience research includes areas focused on elucidating the functions of each subunit in network formation, during which disruptions are a hallmark of motor-neuron diseases. Here, modern concepts and methods from soft condensed matter physics are combined to address the role of subunits as it relates to interfilament forces and phase behavior in neurofilament networks. Significantly, the phase behavior studies reveal that although neurofilament-medium subunits promote nematic liquid crystal hydrogel phase stability with parallel filament orientation, neurofilament-high subunits stabilize the hydrogel in the nematic phase close to the isotropic gel phase with random, crossed-filament orientation. This indicates a regulatory role for neurofilament-high subunits in filament orientational plasticity required for organelle (e.g., membrane-bound vesicle or mitochondrion) transport along microtubules embedded in neurofilament hydrogels. Future studies—for example, on neurofilament subunits mixed with tubulin and microtubule-associated proteins—should lead to a deeper understanding of forces and heterogeneous structures in neuronal cytoskeletons.


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