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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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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
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Fig2: 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

Mentions: Acute axonal degeneration, focal axonal degeneration and Wallerian degeneration appear to be specific morphological expressions of a cumulative number of underlying molecular mechanisms. We review here some of the most important and so far best-characterized molecular mechanisms that form the backbone of the degenerative cascade (summarized in Fig. 2).Fig. 2


Axonal degeneration as a therapeutic target in the CNS.

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

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
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: 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
Mentions: Acute axonal degeneration, focal axonal degeneration and Wallerian degeneration appear to be specific morphological expressions of a cumulative number of underlying molecular mechanisms. We review here some of the most important and so far best-characterized molecular mechanisms that form the backbone of the degenerative cascade (summarized in Fig. 2).Fig. 2

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