Wallerian degeneration
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2008-07-07T16:31:34Z
VolkovBot
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robot Adding: [[pl:Zwyrodnienie Wallera]]
If a [[nerve fiber]] is cut or crushed, the part [[distal]] to the injury (i.e. the part of the [[axon]] separated from the [[neuron]]'s [[cell nucleus]]) will degenerate, in a process known as '''Wallerian degeneration'''.<ref>[http://missinglink.ucsf.edu/lm/ids_104_cns_injury/Response%20_to_Injury/WallerianDegeneration.htm Trauma and Wallerian Degeneration], [[University of California, San Francisco]]</ref> This is also known as anterograde degeneration.
Wallerian Degeneration occurs after axonal injury 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| myelin sheath]] and infiltration by [[macrophage]]s. The macrophages, accompanied by [[Schwann cells]], serve to clear the debris from the degeneration.<ref name = "one"> Waller A. “Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres.” Philos. Trans. R. Soc. London 1850, 140:423–29 </ref><ref> 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. </ref>
The nerve fiber's [[neurolemma]] does not degenerate and remains as a hollow tube. Within 96 hours of the injury, the proximal end of the nerve fiber 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 1-3 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. This regeneration however happens only in PNS, not in the [[spinal cord]]. The crucial difference is that in the CNS, including in the spinal cord, myelin sheaths are produced by [[oligodendrocyte]]s and not by Schwann cells.
==History==
Wallerian degeneration is named after [[Augustus Volney Waller]]. Waller experimented on [[frog]]s in 1850, by
severing their [[glossopharyngeal nerve|glossopharyngeal]] and [[hypoglossal nerve|hypoglossal]] nerves. He then observed the distal nerves from the site of injury,
which were separated from their cell bodies in the brain stem.<ref name ="one"/>
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.<ref >Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T. “In vivo imaging of axonal degeneration and regeneration in the injured spinal cord.” Nat. Med. 11(2005):572–77. </ref>
Degeneration follows with swelling of the [[axolemma]], and eventually leads to bead like formation.
The process takes about roughly 24 hours 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.<ref name = "four"> Vargas, M.E., Barres, B. A. “Why is Wallerian Degeneration in the CNS so slow.” Annual Review of Neuroscience, 2007. 30: 153-79. </ref>
Granular disintegration of the axonal cytoskeleton and inner [[organelle]]s occurs after axolemma degradation.
Early changes include accumalation of [[mitochondria]] in the [[Nodes of Ranvier|paranodal regions]] at the site of injury.
[[Endoplasmic reticulum]] degrades and mitochondria swell up and eventually disintegrate.
The depolymerization of [[microtubule]]s occurs and is soon followed by degradation of
the neurofilaments and other cytoskeleton components. The disintegration is
dependent on [[Ubiquitin]] and [[Calpain]] proteases (caused by influx of calcium ion), suggesting that
axonal degeneration is an active process and not a passive one as previously misunderstood.<ref >Zimmerman UP, Schlaepfer WW. “Multiple forms of Ca-activated protease from rat brain and muscle.” Journal of Biological Chemistry, 1984. 259:3210–8. </ref>
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.<ref name = "four"/>
===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). <ref> Guertin AD, Zhang DP, Mak KS, Alberta JA, Kim HA. “Microanatomy of axon/glial signaling duringWallerian degeneration.” Journal of Neuroscience, 2005. 25:3478–87</ref>
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.<ref name = "four"/> 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 antibodies.<ref> Vargas ME, Singh SJ, Barres BA. “Why is Wallerian degeneration so slow in the CNS.” Soc. Neurosci., 2005. Program No. 439.2 </ref>
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 system|complement]], [[pentraxins]], and [[antibodies]]. However, only complement has shown to
help in myelin debris phagocytosis.<ref>Dailey AT, Avellino AM, Benthem L, Silver J, Kliot M. “Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration. J. Neurosci., 1998. 18:6713–22.</ref>
Murinson et al (2005)<ref>Murinson BB, Archer DR, Li Y, Griffin JW. “Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents.” Journal of Neuroscience, 2005. 25:1179–87. </ref> 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.<ref >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</ref>
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 underwent [[apoptosis]].<ref> Barres BA, Jacobson MD, Schmid R, Sendtner M, Raff MC. “Does oligodendrocyte survival depend on axons?” Curr. Biol., 1993. 3:489–97.</ref>
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
<ref> Ludwin SK. “Oligodendrocyte survival in Wallerian degeneration.” Acta Neuropathol., 1990. 80:184–91</ref>,
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.<ref>Koshinaga M, Whittemore SR. “The temporal and spatial activation of microglia in fiber tracts undergoing anterograde and retrograde degeneration following spinal cord lesion.” J. Neurotrauma, 1995. 12:209–22. </ref>
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. <ref name = "four"/>
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.<ref>George R, Griffin JW. “Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model.” Exp. Neurol., 1994. 129:225–36. </ref>
==Regeneration==
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.<ref> He Z, Koprivica V. “The Nogo signaling pathway for regeneration block.” Annu. Rev. Neurosci., 2004. 27:341–68. </ref>
An experiment conducted on [[Newt]]s, animals which 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.<ref> Turner JE, Glaze KA. “The early stages of Wallerian degeneration in the severed optic nerve of the Newt (Triturus viridescens)” Anat. Rec., 1976. 187:291–310. </ref>
===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.<ref>Heumann R, Korsching S, Bandtlow C, Thoenen H. “Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection.” J. Cell Biol., 1987. 104:1623–31. </ref>
Macrophages also stimulate Schwann cells and fibroblasts to produce NGF via macrophage-derived interleukin-1.<ref>Lindholm D, Heumann R, Hengerer B, Thoenen H. “Interleukin 1 increases stability and transcription of mRNA encoding nerve growth factor in cultured rat fibroblasts.” J. Biol. Chem., 1988. 263:16348–51. </ref>
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.<ref name = "four"/> 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.<ref>Thomas PK, King RH. “The degeneration of unmyelinated axons following nerve section: an ultrastructural study.” J. Neurocytol., 1974. 3:497–512. </ref>
Schwann cells upregulate the production of cell surface adhesion molecule ninjurin further
promoting growth.<ref> Araki T, Milbrandt J. “Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth.” Neuron, 1996. 17:353–61.</ref>
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==
[[house mouse|Mice]] belonging to the strain C57BL/''Wld<sup>s</sup>'' have delayed Wallerian degeneration,<ref>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.</ref>
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 ''Wld<sup>s</sup>'' strain of mice. The mutation occurred first in mice in
Harlan-Olac, a laboratory producing animals the United Kingdom. The ''Wld<sup>s</sup>'' mutation
is an [[Dominance relationship|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 acid]]s is also part of the mutation.<ref name = "twenty three">Coleman MP, Conforti L, Buckmaster EA,Tarlton A, Ewing RM, et al. “An 85-kb tandem triplication in the slow Wallerian degeneration (Wlds) mouse.” Proc. Natl. Acad. Sci. USA, 1998. 95:9985–90. </ref>
The protein created, localizes within the nucleus and is undetectable in axons.<ref> Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, et al. “Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.” Nat. Neurosci., 2001. 4:1199–206</ref>
===Effects of 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. Initially it was suspected that the
''Wld<sup>s</sup>'' mutation slows down the macrophage infiltration, but recent studies suggest that the mutation protects axons rather than
slowing down the macrophages.<ref name = "twenty three"/> The process by which the axonal protection is achieved is
poorly understood. However, studies<ref name = "twenty five">Araki T, Sasaki Y, Milbrandt J. “Increased nuclearNADbiosynthesis and SIRT1activation prevent axonal degeneration.” Science, 2004. 305:1010–13.</ref> suggest that the ''Wld<sup>s</sup>'' mutation leads to overexpression of the Nmnat-1 protein, which
leads to increased [[Nicotinamide adenine dinucleotide|NAD]] synthesis. This in turn activates
SIRT1-dependent process within the nucleus causing changes in gene transcription.<ref name="twenty five"/>
NAD<sup>+</sup> by itself provides added axonal protection by increasing the axon's energy resources.<ref>Wang J, Zhai Q, Chen Y, Lin E, Gu W, et al. “A local mechanism mediates NADdependent protection of axon degeneration.” J. Cell Biol., 2005. 170:349–55. </ref> More recent work, however, raises doubt that either NMNAT or NAD can substitute for the full length WldS gene.<ref>Conforti, L., G. Fang, B. Beirowski, M. S. Wang, L. Sorci, S. Asress, R. Adalbert, A. Silva, K. Bridge, X. P. Huang, G. Magni, J. D. Glass and M. P. Coleman (2007). "NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration." Cell Death Differ 14(1): 116-27.</ref> 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. Thus, the underlying biological mechanism accounting for the WldS phenotype remains unknown.
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 ''Wld<sup>s</sup>'' mutated mice,
macrophage infiltration was considerably delayed by up to six to eight days.<ref>Fujiki, M., Zhang, Z., Guth, L., Steward, O. “Genetic Influences on Cellular Reactions to Spinal Cord Injury: Activation of Macrophages/Microglia and Astrocytes Is Delayed in Mice Carrying a Mutation ( Wlds) That Causes Delayed Wallerian Degeneration.” The Journal of Comparative Neurology, 1996. 371:469-84. </ref>
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.
== References==
<references/>
==External links==
* {{MeshName|Wallerian+Degeneration}}
[[Category:Neurological disorders]]
[[de:Wallersche Degeneration]]
[[fr:Dégénérescence wallérienne]]
[[it:Degenerazione walleriana]]
[[ja:ワーラー変性]]
[[pl:Zwyrodnienie Wallera]]
[[tl:Wallerian degeneration]]