Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation

Axonal degeneration causes morbidity in many neurological conditions including stroke, neurotrauma and multiple sclerosis. The limited ability of central nervous system (CNS) neurons to regenerate, combined with the observation that axonal damage causes clinical disability, has spurred efforts to investigate the mechanisms of axonal degeneration. Ca influx from outside the axon is a key mediator of injury. More recently, substantial pools of intra-axonal Ca sequestered in the ‘axoplasmic reticulum’ have been reported. These Ca stores are under the control of multimolecular ‘nanocomplexes’ located along the internodes under the myelin. The overactivation of these complexes during disease can lead to a lethal release of Ca from intra-axonal stores. Rich receptor pharmacology offers tantalizing therapeutic options targeting these nanocomplexes in the many diseases where axonal degeneration is prominent.