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Wallerian degeneration

Wallerian Degeneration results from axonal injury, and occurs in axons in both the Peripheral nervous system (PNS) and Central Nervous System (CNS). It occurs at the distal stump of the site of injury and usually begins within 24 hours of a lesion. Prior to degeneration distal axon stumps tend to remain electrically excitable . After injury, the axonal skeleton disintegrates and the axonal membrane breaks apart. The axonal degeneration is followed by degradation of the myelin sheath and macrophage infiltration. The macrophages, accompanied with Schwann cells serve to clear the debris from the degeneration.[1] [2]



Wallerian degeneration is named after Augustus Volney Waller. Waller conducted his experiment in 1850, on frogs by severing their glossopharyngeal and hypoglossal nerves. He then observed the distal nerves from the site of injury, which were separated from their cell bodies in the brain stem.[1] Waller described the disintegration of myelin, which he referred to as "medulla", into separate particles of various sizes. The degenerated axons formed droplets that could be stained, thus allowing studies of the course of individual nerve fibres.

Axonal Degeneration

Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal injuries initially lead to acute axonal degeneration (AAD), which is rapid separation of the proximal and distal ends within 30 minutes of injury.[3] Degeneration follows with swelling of the axolemma, and eventually leads to bead like formation. The process takes about roughly 24 hrs in the PNS, and longer in the CNS. The signaling pathways leading to axolemma degeneration are currently unknown. However, research has shown that this AAD process is calcium – independent.[4]

Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Early changes include accumalation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulum degrades and mitochondria swell up and eventually disintegrate. The depolymerization of microtubules occurs and is soon followed by degradation of the neurofilaments and other cytoskeleton components. The disintegration is dependent on Ubiquitin and Calpain proteases (casued by influx of calcium ion), suggesting that axonal degeneration is an active process and not a passive one as previously misunderstood.[5] Thus the axon undergoes complete fragmentation. The rate of degradation is dependent on the type of injury and also varies from PNS to CNS, being slower in CNS. Another factor that affects degradation rate includes axon diameter. Larger axons require longer time for cytoskeleton degradation and thus take a longer time to degenerate.

Myelin Clearance

Myelin is a phospholipid membrane that wraps around axons to provide them with insulation. Its produced by Schwann cells in the PNS, and by Oligodendrocytes in the CNS. Myelin clearance is the next step in Wallerian degeneration following axonal degeneration. The cleaning up of myelin debris is different for PNS and CNS. PNS is much faster and efficient at clearing myelin debris in comparison to CNS, and Schwann cells are the primary cause of this difference. Another key aspect is the change in permeability of the blood-tissue barrier in the two systems. In PNS, the permeability increases throughout the distal stump, but the barrier disruption in CNS is limited to just the site of injury.[4]

Clearance in PNS

The response of Schwann cells to axonal injury is rapid. The time period of response is estimated to be prior to the onset of axonal degeneration. Neuregulins are believed to be responsible for the rapid activation. They activate ErbB2 receptors in the Schwann cell microvilli, which results in the activation of the mitogen-activated protein kinase (MAPK). [6] Although MAPK activity is observed, the injury sensing mechanism of Schwann cells is yet to be fully understood. The sensing is followed by decreased synthesis of myelin lipids and eventually stops within 48 hrs. The myelin sheaths separate from the axons at the Schmidt-Lanterman incisures first and then rapidly deteriorate and shorten to form bead-like structures. Schwann cells continue to clear up the myelin debris by degrading their own myelin, phagocytose extracellular myelin and attract macrophages to myelin debris for phagocytosis. [4] However, the macrophages are not attracted to the region for the first few days; hence the Schwann cells take the major role in myelin cleaning until then.

Schwann Cells have been observed to recruit macrophages by release of cytokines and chemokines after sensing of axonal injury. The recruitment of macrophages helps improve the clearing rate of myelin debris. The resident macrophages present in the nerves release further chemokines and cytokines to attract further macrophages. The degenerating nerve also produce macrophage chemotactic molecules. Another source of macrophage recruitment factors is serum. Delayed macrophage recruitment was observed in B-cell deficient mice lacking serum anitbodies. [7] These signaling molecules together cause an influx of macrophages, which peaks during the third week after injury. While Schwann cells mediate the initial stage of myelin debris clean up, macrophages come in to finish the job. Macrophages are facilitated by opsonins, which label debris for removal. The 3 major groups found in serum include complement, pentraxins, and antibodies. However, only complement has shown to help in myelin debris phagocytosis [8]

Murinson et al (2005) [9] observed that non-myelinated or myelinated Schwann cells in contact with an injured axon enter cell cycle thus leading to proliferation. Observed time duration for Schwann cell divisions where approximately 3 days after injury. [10] Possible sources of proliferation signal are attributed to the ErbB2 receptors and the ErbB3 receptors. This proliferation could further enhance the myelin cleaning rates and plays an essential role in regeneration of axons observed in PNS. Schwann cells emit growth factors which attract new axonal sprouts growing from the proximal stump after complete degeneration of the injured distal stump. This leads to possible reinnervation of the target cell or organ. However, the reinnervation is not necessarily perfect as possible misleading occurs during reinnervation of the proximal axons to target cells.

Clearance in CNS

In comparison to Schwann cells, Oligodendrocytes require axon signals to survive. In their developmental stages, oligodendrocytes that failed to make contact to axon and receive any axon signals under went apoptosis. [11] Experiments in wallerian degeneration have shown that upon injury oligodendrocytes either under go programmed cell death or enter a state of rest. Therefore, unlike Schwann cells, oligodendrocytes fail to clean up the myelin sheaths and their debris. In experiments conducted on rats [12], myelin sheaths were found for up to 22 months. Therefore, CNS rates of myelin sheath clearance are very slow and could possibly be the cause for hindrance in the regeneration capabilities of the CNS axons as no growth factors are available to attract the proximal axons. Another feature that results eventually is Glial scar formation. This further hinders chances for regeneration and reinnervation.

Oligodendrocytes fail to recruit macrophages for debris removal. Macrophage entry in general into CNS site of injury is very slow. In contrast to PNS, Microglia play a vital role in CNS wallerian degeneration. However, their recruitment is slower in comparison to macrophage recruitment in PNS by approximately 3 days. Further, microglia might be activated but hypertrophy, and fail to transform into fully phagocytic cells. Those microglia that do transform, clear out the debris effectively. Differentiating phagocytic microglia can be accomplished by testing for expression of Major histocompatibility complex (MHC) class I and II during wallerian degeneration. [13] The rate of clearance is very slow among microglia in comparison to macrophages. Possible source for variations in clearance rates could include lack of opsonin activity around microglia, and the lack of increased permeability in the blood-brain barrier. The decreased permeability could further hinder macrophage infiltration to the site of injury. [4]

These findings have suggested that the delay in wallerian degeneration in CNS in comparison to PNS is caused not due to a delay in axonal degeneration, but rather is due to the difference in clearance rates of myelin in CNS and PNS. [14]


Regeneration follows degeneration. Regeneration is rapid in PNS, and might need some grafts for appropriate reinnervation. It is supported by Schwann cells through growth factors release. CNS regeneration is much slower, and is almost absent in most species. The primary cause for this could be the delay in clearing up myelin debris. Myelin debris, present in CNS or PNS, contains several inhibitory factors. The elongated presence of myelin debris in CNS could possibly hinder the regeneration. \ [15] An experiment conducted on Newt, an animal with fast CNS axon regenerationc capabilities, found that wallerian degeneration of an optic nerve injury took upto 10 to 14 days on average, further suggesting that slow clearance inhibits regeneration.[16]

Schwann cells and Endoneural Fibroblasts in PNS

In healthy nerves, Nerve growth factor (NGF) is procuded in very small amounts. However, upon injury, NGF mRNA expression increases by five to seven fold within a period of 14 days. Nerve fibroblasts and Schwann cells play an important role in increased expression of NGF mRNA.[17] Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1. [18] Other neurotrophic molecules produced by Schwann cells and fibroblasts together include Brain-derived neurotrophic factor, Glial cell line-derived neurotrophic factor, Ciliary neurotrophic factor, Leukemia inhibitory factor, Insulin-like growth factor, and Fibroblast growth factor. These factors together create a favorable environment for axonal growth and regeneration.[4] Apart from growth factors, Schwann cells also provide structural guidance to further enhance regeneration. During their proliferation phase, Schwann cells begin to form a line of cells called Bands of Bunger within the basal laminar tube. Axons have been observed to regenerate in close association to these cells. [19] Schwann cells upregulate the production of cell surface adhesion molecule ninjurin further promoting growth. [20] These lines of cell guide the axon regeneration in proper direction. The possible source of error that could result from this is possible mismatching of the target cells as discussed earlier.

Due to lack of such favorable promoting factors in CNS, regeneration is stunted in CNS.

Delayed Wallerian Degeneration

Mice belonging to the strain C57BL/Wlds have delayed Wallerian degeneration,[21] and thus allow to study the roles of various cell types and the underlying cellular and molecular processes. Current understanding of the process has been possible via experimentation on the Wlds strain of mice. The mutation occurred first in mice in Harlan-Olac, a laboratory producing animals in United Kingdom. The Wlds mutation is an autosomal dominant mutation occurring in the mouse chromosome 4. The gene mutation is an 85-kb tandem triplication, occurring naturally. The mutated region contains two associated genes: nicotinamide mononucleotide adenlyl transferase 1 (Nmnat-1) and ubiquitination factor e4b (Ube4b). A linker region encoding 18 amino acids is also part of the mutation. [22] The protein created, localizes within the nucleus and is undetectable in axons. [23]

Effects of Mutation

The mutation causes no harm to the mouse. The only known effect is that the Wallerian degeneration is delayed by unto three weeks on average after injury of a nerve. Initially it was suspected that the Wlds mutation slows down the macrophage infiltration. But recent studies suggest that the mutation protects axons rather than slowing down the macrophages. [22] The process by which the axonal protection is achieved is poorly understood. However, studies[24] suggest that the Wlds mutation leads to overexpression of the Nmnat-1 protein, which leads to increased NAD synthesis. This in turn activates SIRT1-dependent process within the nucleus causing changes in gene transcription. [24] NAD+ by itself provides added axonal protection by increasing the axon's energy resources. [25] Thus axonal protection improves in the Wlds mutation mice.

The provided axonal protection delays the onset of Wallerian degeneration. Schwann cell activation would be delayed, and they wouldn't detect axonal degradation signals from ErbB2 receptors. In experiments on Wlds mutated mice, macrophage infiltration was considerably delayed by upto six to eight days. [26] However, once the axonal degradation has begun, degeneration takes its normal course and respective of the nervous system, degradation follows at the above described rates. Possible effects that could result due to this late onset would be weaker regenerative abilities in the mice.


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  2. ^ Michael P. Coleman; Laura Conforti; E. Anne Buckmaster; Andrea Tarlton; Robert M. Ewing; Michael C. Brown; Mary F. Lyon; V. Hugh Perry. “An 85-kb Tandem Triplication in the Slow Wallerian Degeneration (Wld s ) Mouse.” Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 17. (Aug. 18, 1998), pp. 9985-9990.
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  10. ^ Liu HM, Yang LH, Yang YJ. “Schwann cell properties: 3. C-fos expression, bFGF production, phagocytosis and proliferation during Wallerian degeneration." J. Neuropathol. Exp. Neurol., 1995. 54:487–96
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  21. ^ Perry VH, Brown MC, Tsao JW. The Effectiveness of the Gene Which Slows the Rate of Wallerian Degeneration in C57BL/Ola Mice Declines With Age. Eur J Neurosci. 1992;4:1000–1002.
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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Wallerian_degeneration". A list of authors is available in Wikipedia.
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