Figure 1.

Early phase of axon degeneration can appear in different forms.

(A) Established programs of axon degeneration (such as Wallerian degeneration or focal acute axonal degeneration) are calcium-dependent and are finally characterized by the following sequence of events: Initial injury trigger leads to an abnormal calcium influx through mechanochannels/nanopores (1) and calcium release from internal calcium stores, such as mitochondria and axoplasmic reticulum (2). The increase in intra-axonal calcium level activates calcium-dependent calpain proteases (3) that lead to cytoskeletal breakdown and eventually cargo accumulation (4), such as mitochondria and NMNAT2. (B) Astrocytopathy-driven axonal beading has characteristics that distinguish it from the other described pathways. After the lytic depletion of astrocytes (1), a sodium influx-related osmotic challenge (2) induces remodeling of the microtubular cytoskeleton (3) in the initial state without overt cargo accumulation (4). The described processes affect both myelinated and non-myelinated axons. However, for better readability of the figure, the myelin layer has been omitted in the inset illustrations. AQP4: Aquaporin 4 channel; AR: axoplasmic reticulum; MI: mitochondria; MT: microtubules; NMNAT2: the protein nicotinamide mononucleotide adenylyltransferase 2. Created with BioRender.com.