Wallerian degeneration
Nerve injury | |
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Fluorescent micrographs (100x) of Wallerian degeneration in cut and crushed peripheral nerves. Left column is proximal to the injury, right is distal. A and B: 37 hours post cut. C and D: 40 hours post crush. E and F: 42 hours post cut. G and H: 44 hours post crush. | |
Specialty | Neurology |
Wallerian degeneration is an active process of degeneration that results when a
Wallerian degeneration occurs after axonal injury in both the
Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. They finally align in tubes (Büngner bands) and express surface molecules that guide regenerating fibers.[7] Within 4 days of the injury, the distal end of the portion of the nerve fiber proximal to the lesion sends out sprouts towards those tubes and these sprouts are attracted by growth factors produced by Schwann cells in the tubes. If a sprout reaches the tube, it grows into it and advances about 1 mm per day, eventually reaching and reinnervating the target tissue. If the sprouts cannot reach the tube, for instance because the gap is too wide or scar tissue has formed, surgery can help to guide the sprouts into the tubes. Regeneration is efficient in the PNS, with near complete recovery in case of lesions that occur close to the distal nerve terminal. However recovery is hardly observed at all in the spinal cord. One crucial difference is that in the CNS, including the spinal cord, myelin sheaths are produced by oligodendrocytes and not by Schwann cells.
History
Wallerian degeneration is named after Augustus Volney Waller. Waller experimented on frogs in 1850, 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.[5] Waller described the disintegration of myelin, which he referred to as "medulla", into separate particles of various sizes. The degenerating axons formed droplets that could be stained, thus allowing for studies of the course of individual nerve fibres.
Axonal degeneration
Although most injury responses include a
Granular disintegration of the axonal cytoskeleton and inner
Myelin clearance
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.
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 antibodies.
Murinson et al. (2005)[15] 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 were approximately 3 days after injury.[16] 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 that 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 fail to make contact to axon and receive axon signals undergo apoptosis.[17]
Experiments in Wallerian degeneration have shown that upon injury oligodendrocytes either undergo 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,[18] 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.[19] 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.[11]
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.[20]
Regeneration
Regeneration follows degeneration. Regeneration is rapid in PNS, allowing for rates of up to 1 millimeter a day of regrowth.[21] Grafts may also be needed to allow for appropriate reinnervation. It is supported by Schwann cells through growth factors release. CNS regeneration is much slower, and is almost absent in most vertebrate 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 prolonged presence of myelin debris in CNS could possibly hinder the regeneration.[22] An experiment conducted on newts, animals that have fast CNS axon regeneration capabilities, found that Wallerian degeneration of an optic nerve injury took up to 10 to 14 days on average, further suggesting that slow clearance inhibits regeneration.[23]
Schwann cells and endoneural fibroblasts in PNS
In healthy nerves, nerve growth factor (NGF) is produced 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.[24] Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1.[25] 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.[11] 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 Bungner within the basal laminar tube. Axons have been observed to regenerate in close association to these cells.[26] Schwann cells upregulate the production of cell surface adhesion molecule ninjurin further promoting growth.[27] 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.
Wallerian degeneration slow
Although the protein created localizes within the nucleus and is barely detectable in axons, studies suggest that its protective effect is due to its presence in axonal and terminal compartments.[32][33] The protection provided by the WldS protein is intrinsic to the neurons and not surrounding support cells, and is only locally protective of the axon, indicating an intracellular pathway is responsible for mediating Wallerian degeneration.[34][35]
Effects of the WldS mutation
The mutation causes no harm to the mouse. The only known effect is that the Wallerian degeneration is delayed by up to three weeks on average after injury of a nerve. At first, 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.[6] The process by which the axonal protection is achieved is poorly understood. However, studies suggest that the Wlds mutation leads to increased NMNAT1 activity, which leads to increased NAD+ synthesis.[31] This in turn activates SIRT1-dependent process within the nucleus, causing changes in gene transcription.[31] NAD+ by itself may provide added axonal protection by increasing the axon's energy resources.[36] More recent work, however, raises doubt that either NMNAT1 or NAD+ can substitute for the full length Wlds gene.[37] These authors demonstrated by both in vitro and in vivo methods that the protective effect of overexpression of NMNAT1 or the addition of NAD+ did not protect axons from degeneration. However, later studies showed that NMNAT1 is protective when combined with an axonal targeting peptide, suggesting that the key to the protection provided by WldS was the combination of NMNAT1's activity and the axonal localization provided by the N-terminal domain of the chimeric protein.[38]
The provided axonal protection delays the onset of Wallerian degeneration. Schwann cell activation should therefore be delayed, as they would not detect axonal degradation signals from ErbB2 receptors. In experiments on Wlds mutated mice, macrophage infiltration was considerably delayed by up to six to eight days.[39] 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 of this late onset are weaker regenerative abilities in the mice. Studies indicate that regeneration may be impaired in WldS mice, but this is likely a result of the environment being unfavorable for regeneration due to the continued existence of the undegenerated distal fiber, whereas normally debris is cleared, making way for new growth.[40]
SARM1
The Wallerian degeneration pathway has been further illuminated by the discovery that sterile alpha and TIR motif containing 1 (SARM1) protein plays a central role in the Wallerian degeneration pathway. The gene was first identified in a Drosophila melanogaster mutagenesis screen, and subsequently knockouts of its homologue in mice showed robust protection of transected axons comparable to that of WldS.[41][42]
SARM1 catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose.[43] SARM1 activation locally triggers a rapid collapse of NAD+ levels in the distal section of the injured axon, which then undergoes degeneration.[44] This collapse in NAD+ levels was later shown to be due to SARM1's TIR domain having intrinsic NAD+ cleavage activity.[45] The SARM1 protein has four domains, a mitochondrial localization signal, an auto-inhibitory N-terminus region consisting of armadillo/HEAT motifs, two sterile alpha motifs responsible for multimerization, and a C-terminus Toll/Interleukin-1 receptor that possesses enzymatic activity.[45] Activation of SARM1 is sufficient to collapse NAD+ levels and initiate the Wallerian degeneration pathway.[44]
The activity of SARM1 helps to explain the protective nature of the survival factor NMNAT2, as NMNAT enzymes have been shown to prevent SARM1-mediated depletion of NAD+.[46] This relationship is further supported by the fact that mice lacking NMNAT2, which are normally not viable, are completely rescued by SARM1 deletion, placing NMNAT2 activity upstream of SARM1.[47] Other pro-degeneration signaling pathways, such as the MAP kinase pathway, have been linked to SARM1 activation. MAPK signaling has been shown to promote the loss of NMNAT2, thereby promoting SARM1 activation, although SARM1 activation also triggers the MAP kinase cascade, indicating some form of feedback loop exists.[48][49] One explanation for the protective effect of the WldS mutation is that the NMNAT1 region, which is normally localized to the soma, substitutes for the labile survival factor NMNAT2 to prevent SARM1 activation when the N-terminal Ube4 region of the WldS protein localizes it to the axon. The fact that the enhanced survival of WldS axons is due to the slower turnover of WldS compared to NMNAT2 also helps explain why SARM1 knockout confers longer protection, as SARM1 will be completely inactive regardless of inhibitor activity whereas WldS will eventually be degraded. Possibles implications of the SARM1 pathway in regard to human health may be found in animal models which exhibit traumatic brain injury, as mice which contain Sarm1 deletions in addition to WldS show decreased axonal damage following injury.[50] Specific mutations in NMNAT2 have linked the Wallerian degeneration mechanism to two neurological diseases.
See also
- Axonotmesis
- Connective tissue in the peripheral nervous system
- Diffuse axonal injury
- Digestion chambers
- Nerve injury
- Neuroregeneration
- Peripheral nerve injury
- Primary and secondary brain injury
- Seddon's classification
- Spinal cord injury research
References
- ^ Trauma and Wallerian Degeneration, University of California, San Francisco
- PMID 20345246.
- PMID 20126265.
- PMID 28445802.
- ^ JSTOR 108444.
- ^ PMID 9707587.
- S2CID 24140507.
- S2CID 25287010.
- PMID 9592084.
- PMID 22232700.
- ^ PMID 17506644.
- PMID 6321500.
- PMID 15800203.
- PMID 9712643.
- PMID 15689554.
- S2CID 25055891.
- S2CID 39909326.
- S2CID 36103242.
- PMID 7629867.
- S2CID 40089749.
- ISBN 978-1-4160-2578-8.
- PMID 15217336.
- S2CID 2028827.
- PMID 3034917.
- PMID 3263368.
- S2CID 37385200.
- S2CID 12471778.
- S2CID 24786532.
- ^ Perry, V. H., Lunn, E. R., Brown, M. C., Cahusac, S. and Gordon, S. (1990), Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene. European Journal of Neuroscience, 2: 408-413. https://doi.org/10.1111/j.1460-9568.1990.tb00433.x
- PMID 8415768.
- ^ S2CID 32370137.
- S2CID 8316115.
- PMID 19158292.
- S2CID 45871975.
- S2CID 25359698.
- PMID 16043516.
- PMID 16645633.
- PMID 20926655.
- S2CID 8797673.
- S2CID 37501852.
- PMID 22678360.
- PMID 23946415.
- PMID 31672920.
- ^ PMID 25908823.
- ^ PMID 28334607.
- PMID 27735788.
- PMID 28978465.
- PMID 25594179.
- PMID 28095293.
- PMID 26912636.
External links
- Wallerian+Degeneration at the U.S. National Library of Medicine Medical Subject Headings (MeSH)