Axonal degeneration as a therapeutic target in the CNS

Abstract

Degeneration of the axon is an important step in the pathomechanism of traumatic, inflammatory and degenerative neurological diseases. Increasing evidence suggests that axonal degeneration occurs early in the course of these diseases and therefore represents a promising target for future therapeutic strategies. We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders. We discuss the basic morphological and temporal modalities of axonal degeneration (acute, chronic and focal axonal degeneration and Wallerian degeneration). Based on the mechanistic concepts, we then delineate in detail the major molecular mechanisms that underlie the degenerative cascade, such as calcium influx, axonal transport, protein aggregation and autophagy. We finally concentrate on putative therapeutic targets based on the mechanistic prerequisites.

Fig. 1

a Micrographs of a rat optic nerve axon labelled with enhanced green fluorescent protein expressed by an intravitreally injected viral vector at given time points (in min) after optic nerve crush (proximal to the crush site). b Quantification of the axonal integrity ratio (sum length of the remaining axonal fragments divided by initial length of the intact axon segment) of the axon in a. c Representation of the morphological events observed in acute axonal degeneration. A crush lesion of an axon of the central nervous system leads to a rapid increase of intracellular calcium concentrations within the first 30-40 s after lesion. Misalignment of neurofilaments and disruption of microtubules followed by local accumulations of organelles attributable to dysfunctional axonal transport and the subsequent formation of axonal bulbs can be seen within the next 30-120 min. This is then followed by the appearance of a high number of autophagic vacuoles and the fragmentation of the axon spanning over 400 μm proximal and distal from the crush site

Fig. 2

Representation of selected molecular mechanisms involved in axonal degeneration. Intra-axonal calcium levels can rise by the entry of calcium from the extra-axonal space, e.g. through calcium channels and disrupted axonal membranes, and from intra-axonal sources, e.g. mitochondria or endoplasmic reticulum (not shown). Calcium-dependent proteins, such as calpain, are activated and cleave target proteins, e.g. microtubules or collapsin response mediator protein-2 (CRMP-2). This in turn can result in axonal transport impairment. Autophagy is induced in a calcium-dependent manner and results in the degradation of proteins and organelles