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Axonal degeneration as a therapeutic target in the CNS.

Lingor P, Koch JC, Tönges L, Bähr M - Cell Tissue Res. (2012)

Bottom Line: We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medicine Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. plingor@gwdg.de

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.

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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
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Fig1: 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

Mentions: The term acute axonal degeneration refers to a rapid axonal disintegration within several hours following a traumatic lesion in the CNS. It is confined to the adjacent 300–400 μm of the proximal and distal end of the axon and has been described for the spinal cord (Kerschensteiner et al. 2005) and the optic nerve (Knöferle et al. 2010). In both cases, it has been visualized by using in vivo live-imaging techniques. Although the time kinetics differ slightly between the model systems, being faster in the mouse spinal cord than in the rat optic nerve, the sequential morphological changes and the undelying mechanisms seem to be similar in both tissues (summarized in Fig.1).Fig. 1


Axonal degeneration as a therapeutic target in the CNS.

Lingor P, Koch JC, Tönges L, Bähr M - Cell Tissue Res. (2012)

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
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375418&req=5

Fig1: 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
Mentions: The term acute axonal degeneration refers to a rapid axonal disintegration within several hours following a traumatic lesion in the CNS. It is confined to the adjacent 300–400 μm of the proximal and distal end of the axon and has been described for the spinal cord (Kerschensteiner et al. 2005) and the optic nerve (Knöferle et al. 2010). In both cases, it has been visualized by using in vivo live-imaging techniques. Although the time kinetics differ slightly between the model systems, being faster in the mouse spinal cord than in the rat optic nerve, the sequential morphological changes and the undelying mechanisms seem to be similar in both tissues (summarized in Fig.1).Fig. 1

Bottom Line: We review the evidence for axonal destruction from pathological findings and animal models with particular emphasis on neurodegenerative and neurotraumatic disorders.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University Medicine Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. plingor@gwdg.de

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.

Show MeSH
Related in: MedlinePlus