Axonal swellings (AS) are one of the neuropathological hallmark of axonal injury in several disorders from trauma to neurodegeneration. Current evidence proposes a role of perturbed Ca2+ homeostasis in AS formation, involving impaired axonal transport and focal distension of the axons. Mechanisms of AS formation, in particular moments following injury, however, remain unknown. Here we show that AS form independently from intra-axonal Ca2+ changes, which are required primarily for the persistence of AS in time. We further show that the majority of axonal proteins undergoing de/phosphorylation immediately following injury belong to the cytoskeleton. This correlates with an increase in the distance of the actin/spectrin periodic rings and with microtubule tracks remodeling within AS. Observed cytoskeletal rearrangements support axonal transport without major interruptions. Our results demonstrate that the earliest axonal response to injury consists in physiological adaptations of axonal structure to preserve function rather than in immediate pathological events signaling axonal destruction.

Biostatistics Department International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Department of Neurosciences Mayo Clinic Rochester MN USA

Division of Neurology University Medical Centre Ljubljana Slovenia

Proteomics and Mass Spectrometry Core Lab International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Translational Neuroscience and Ageing Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

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