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JOURNAL OF NEUROCHEMISTRY
| 2009 | 108 | 23–32
doi: 10.1111/j.1471-4159.2008.05754.x
The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4072, Australia
Abstract
Axonal degeneration is a common hallmark of both nerve
injury and many neurodegenerative conditions, including
motor neuron disease, glaucoma, and Parkinson’s, Alzheimer’s, and Huntington’s diseases. Degeneration of the
axonal compartment is distinct from neuronal cell death, and
often precedes or is associated with the appearance of the
symptoms of the disease. A complementary process is the
regeneration of the axon, which is commonly observed following nerve injury in many invertebrate neurons and in a
number of vertebrate neurons of the PNS. Important dis-
Different triggers of axonal degeneration
Degeneration of the axon has been observed in at least four
different conditions: nerve trauma, toxic insults, neurodegenerative diseases, and normal neuronal development
(pruning). Axonal truncation as a result of injury causes
degeneration of the distal part of the axon that is detached
from the cell body. This process, which proceeds in a
characteristic and orderly way in which the axon beads,
fragments and is finally removed, is commonly referred to as
Wallerian degeneration (Waller 1850). It was originally
thought that the degeneration of the distal fragment of a
severed axon was a passive process due to the lack of trophic
support from the cell body. However this concept was
challenged in 1989, when Lunn et al. identified a strain of
mice, WldS, which displays a much slower rate of axonal
degeneration following damage (Lunn et al. 1989). In these
animals, the axons survive and maintain function for up to
3 weeks, rather than a few days as observed in wild-type
severed axons. The acquired survival capacity of the injured
neuronal processes of WldS mutants revealed that the distal
axons degenerate actively by triggering a degeneration
program, and not by passive lack of support from the cell
body. It was later shown that the WldS protective effect also
extends to axons and synapses of the CNS (Ludwin and
Bisby 1992; Gillingwater et al. 2006).
coveries, together with innovative imaging techniques, are
now paving the way towards a better understanding of the
dynamics and molecular mechanisms underlying these two
processes. In this study, I will discuss these recent findings,
focusing on the balance between axonal degeneration and
regeneration.
Keywords: axonal regeneration, neurodegenerative diseases, pruning, spinal cord injury, Wallerian degeneration,
WldS.
J. Neurochem. (2009) 108, 23–32.
In addition to mechanical injury, several chemical and
toxic insults, including acrylamide, the anticancer drug
vincristine, the antibiotic nitrofurantoin, and heavy metals,
can cause axonal degeneration and peripheral neuropathy
(Prineas 1969; Schlaepfer 1971; Spencer and Schaumburg
1974; Wang et al. 2000; Rubens et al. 2001; Silva et al.
2006). In these cases, axons ‘die back’; with the degenerating
phenotypes appearing first on the distal segment of the axon,
before progressing proximally toward the cell body (Cavanagh 1964). This dying back phenotype can be generated by
damage occurring directly to the distal part of the axon, as a
consequence of damage to the mid section of the axon
inducing degeneration of the distal fragment, or as a
secondary effect of damage to the neuronal cell body
(reviewed in Coleman 2005; Conforti et al. 2007a).
Received August 8, 2008; revised manuscript received October 13,
2008; accepted October 21, 2008.
Address correspondence and reprint requests to Massimo A. Hilliard,
Queensland Brain Institute, The University of Queensland, Brisbane,
Qld 4072, Australia. E-mail: [email protected]
Abbreviations used: ALS, amyotrophic lateral sclerosis; CED, cell
death abnormality; db-cAMP, dibutyryl-cAMP; DRG, dorsal root ganglia; M cell, Mauthner cell; Nmnat1, NMN adenylyltransferase 1; Ufd2a,
ubiquitin fusion degradation protein 2a; UPS, ubiquitin proteasome
complex; VCP, vasolin-containing protein.
Ó 2008 The Author
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23
24 | M. A. Hilliard
In recent years, axonal degeneration has been proposed to
be a leading or contributing cause of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS),
spinal muscular atrophy, multiple sclerosis, glaucoma, and
Alzheimer’s and Parkinson’s diseases (Trapp et al. 1998;
Cifuentes-Diaz et al. 2002; Fischer et al. 2004; Stokin et al.
2005; Schlamp et al. 2006; Reviewed in Raff et al. 2002 and
Conforti et al. 2007a). In these conditions, axonal degeneration often occurs in a dying-back fashion and is frequently
characterized by intracellular protein accumulation. Aggregates of tau, neurofilaments, and a-synuclein are found in the
neuronal tissues of Alzheimer’s, Huntington’s, and Parkinson’s disease patients, respectively. In a number of neurodegenerative conditions, axonal degeneration overlaps with
degeneration of the cell body (neuronal cell death and
apoptosis) and the causal relationship between these events
and the symptoms of the disease are not always clear
(reviewed in Raff et al. 2002 and Conforti et al. 2007a).
However, genetic evidence indicates that axonal degeneration and neuronal cell death are distinct events. In a mouse
model of progressive motor neuropathy (pmn mice), the
mutant animals develop a neuropathy in which the axons of
motor neurons die back and the neurons undergo apoptosis
(Sagot et al. 1995). The animals die at around 6 weeks after
progressive weakening. Interestingly, when cell death is
genetically inhibited by over-expression of bcl-2 in motor
neurons, axonal degeneration still occurs, and the onset and
progression of the disease, as well as the time of death,
remain the same (Sagot et al. 1995). Recent studies using the
superoxide dismutase 1 (SOD1) transgenic mouse model of
ALS, also mutated in the proapoptotic gene Bax, further
support the idea that the clinical symptoms of ALS result
specifically from damage to the distal motor axon and not
from activation of the cell death pathway (Gould et al. 2006).
These studies separate axonal degeneration from neuronal
cell death and indicate that axonal degeneration is the leading
cause of the disease.
Finally, axonal degeneration also occurs during normal
development of the nervous system when neurons lose some of
their branches in a process known as ‘pruning’. Many neurons
extend their processes in a redundant and excessive manner
and some of these branches are selectively removed to achieve
the final organized and complex connectivity of the circuit.
Pruning has been observed during nervous system development in vertebrates, as well as in invertebrates, such as
Drosophila and Caenorhabditis elegans, and this mechanism
is necessary to generate a precise neural circuit with flawless
neuronal connections (O’Leary and Koester 1993; Lee et al.
1999; Kage et al. 2005; Luo and O’Leary 2005).
Great efforts are being made to discover the molecular
machinery underlying the axonal degeneration process, and
to determine if the molecular components employed are the
same when axonal degeneration is triggered by different
conditions. This is a crucial step needed for a full
understanding of this highly dynamic process, and some
important recent developments are discussed below.
Molecular mechanisms of axonal degeneration
After its initial discovery in mice (Lunn et al. 1989), WldS
was also found to protect physically injured axons in rats
(Adalbert et al. 2005), as well as in invertebrate systems, as
shown for different classes of surgically severed Drosophila
olfactory receptor neurons (Hoopfer et al. 2006; MacDonald
et al. 2006). Furthermore, the protective effect of WldS is not
only restricted to physically injured axons, but also extends
to axons damaged by toxic insults and neurodegenerative
diseases. In mice, WldS can delay axonal degeneration and
neuropathy induced with the toxic agents taxol or vincristine
(Wang et al. 2001, 2002a), as well as with 6-hydroxydopamine (6-OHDA), which generates a Parkinson-like disease
(Sajadi et al. 2004). Similarly, a WldS protective effect has
been observed in mouse models of different neurodegenerative diseases, including progressive motor neuropathy (pmn
mice; Ferri et al. 2003), Charcot–Marie–Tooth disease
(myelin protein zero null mutants; Samsam et al. 2003),
and gracile axonal dystrophy (gad mutant mice; Mi et al.
2005). However, the role of WldS is not universal as it cannot
protect degenerating axons in either the SOD1 transgenic
mouse model of ALS (Vande Velde et al. 2004; Fischer et al.
2005), or the proteolipid protein (Plp) null animal model of
hereditary spastic paraplegia (Edgar et al. 2004). In addition,
in both Drosophila and mice, WldS cannot prevent developmentally regulated axonal pruning (Hoopfer et al. 2006).
These lines of evidence indicate an overlap among the
mechanisms underlying different axonal degeneration events,
but also suggest the existence of alternative, as yet undiscovered, axonal degeneration pathways (Fig. 1). In principle,
alternative pathways might exist because of different triggering conditions, different neuronal types, or different developmental stages. In mice, the same class of neurons (retinal
ganglion cells) undergoing pruning (and thus not protected by
WldS), if physically severed at the same stage, undergo
Wallerian degeneration that can be delayed by WldS (Hoopfer
et al. 2006). At least in this case, the triggering mechanisms
seem crucial for the activation of specific pathways sensitive
or insensitive to WldS-mediated protection.
Positional cloning has revealed that the dominant WldS
mutation is an 85 kb tandem triplication that results in the
production of a chimeric molecule (WldS protein), which
includes the N-terminal 70 amino acids of the ubiquitin fusion
degradation protein 2a (Ufd2a), the complete sequence of the
NAD+ synthesizing enzyme NMN adenylyltransferase 1
(Nmnat1), and a linker region of 18 amino acids (Lyon et al.
1993; Coleman et al. 1998; Conforti et al. 2000; Mack et al.
2001). Considerable experimental evidence suggests an
important role of Nmnat1 and the NAD+ pathway in
protecting axons from degeneration (Araki et al. 2004; Wang
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Journal Compilation Ó 2008 International Society for Neurochemistry, J. Neurochem. (2009) 108, 23–32
Axonal degeneration and regeneration | 25
(a) Injury: vertebrates and invertebrates
Pruning
Neurodegenerative conditions: SOD-1, Plp
Toxic insults: vincristine, taxol, 6-OHDA
Neurodegenerative conditions: pmn, P0, gad
WldS
Degenerating axon
(b) Injury: vertebrates and invertebrates
Pruning
Neurodegenerative conditions: gad, parkin
UPS
Degenerating axon
CED-1/Draper, CED-6
Removed axonal fragments
Fig. 1 Schematic diagram illustrating the overlap of the molecular
components in axonal degeneration occurring under different conditions. (a) WldS can significantly delay axonal degeneration following
injury or toxic insults and in some neurodegenerative conditions
[progressive motor neuropathy (pmn), myelin protein zero (P0), gracile
axonal dystrophy (gad) mice]. In contrast it has no effects in pruning,
and in mouse models of ALS (superoxide dismutase 1; SOD-1 mice)
and spastic paraplegia (Plp mice). (b) The UPS (ubiquitin proteasome
system) underlies axonal degeneration in both vertebrates and invertebrates in injury and pruning, and in some neurodegenerative conditions. The removal of axonal fragments resembles the removal of
apoptotic cell corpses, and is mediated by the cell death genes CED-1/
Draper and CED-6.
et al. 2005; Sasaki et al. 2006). In the WldS mutation, part of
the protective effect could arise from the over-expression of
Nmnat1 with a consequent increase in NAD+ levels (Araki
et al. 2004). Araki et al. have also shown that the sirtuin
silent mating type information regulation 1 (SIRT1), a NAD+dependent histone deacetylase (the mammalian ortholog of
Sir2), is a downstream effector of Nmnat1 activation that
leads to axonal protection. A particularly interesting and
relevant finding is that resveratrol, a polyphenol found in red
grapes and an enhancer of silent mating type information
regulation 2 activity, is able to mimic the axonal protective
effect of NAD+ (Araki et al. 2004). However, in different
conditions Nmnat1 alone cannot fully recapitulate the effect
of the WldS mutation, suggesting the involvement of other
components of the chimera protein (Conforti et al. 2007b;
Watanabe et al. 2007).
Extensive data indicate that the ubiquitin proteasome
system (UPS) is a critical player in axonal degeneration,
although its role appears more complex (Fig. 1) (Saigoh
et al. 1999; Zhai et al. 2003; Watts et al. 2003; reviewed in
Korhonen and Lindholm 2004; Hoopfer et al. 2006). In
Drosophila, axonal pruning and axonal degeneration following injury depend on a functional UPS (Watts et al. 2003;
Hoopfer et al. 2006). Similarly in rat, axonal degeneration
following injury is delayed by inhibition of the UPS (Zhai
et al. 2003). In the WldS mutation, the truncated UPS
molecule (Ufd2a) might function as a dominant negative and
provide some axonal protection. However, different mutations reducing the function of UPS molecules can also be the
cause of neurodegenerative diseases and axonal degeneration, as observed in Parkinson’s disease patients carrying
mutations in the gene parkin (ubiquitin-protein ligase)
(Kitada et al. 1998; Shimura et al. 2000) and in gad mice
(ubiquitin carboxy-terminal hydrolase-L1) (Saigoh et al.
1999). This apparent paradox of UPS functioning in both
directions (degeneration–protection) could be explained by
different levels of UPS triggering diverse responses, by UPS
having alternative effects in different neuronal compartments
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26 | M. A. Hilliard
(cell body, axon, or synapse), or by mutation in different
components of the UPS in turn affecting different molecular
substrates. Recent important findings have shown that the
N-terminal 70 amino acids of WldS bind directly to vasolincontaining protein (VCP/p97), a protein with a key role in the
ubiquitin proteasome system (Laser et al. 2006). Interaction
with WldS targets VCP in discrete intranuclear foci where
other UPS components can also accumulate (Laser et al.
2006). Thus, the N-terminal domain of WldS influences the
intranuclear location of the ubiquitin proteasome as well as
its intrinsic NAD+ synthesis activity, although VCP itself can
also regulate WldS intracellular distribution (Wilbrey et al.
2008). Differential proteomics analysis on isolated synaptic
preparations from the striatum in mice has revealed 16
proteins with modified expression levels in WldS synapses
(Wishart et al. 2007). Interestingly, downstream protein
changes were found in pathways corresponding to both
Ufd2a (including ubiquitin-activating enzyme 1) and Nmnat1
(including voltage-dependent anion-selective channel protein
and aralar1, calcium-binding mitochondrial carrier protein)
(Wishart et al. 2007). Furthermore, increased expression of a
broad spectrum of cell cycle-related genes was found in the
cerebellum of WldS mice and in WldS-expressing human
embryonic kidney 293 cells (Wishart et al. 2008), suggesting
a correlation between modified cell cycle pathways and
altered vulnerability of axons.
Recently, axonal pruning and axonal degeneration following injury have been shown to have other common effectors.
Cell death abnormality (CED)-1/Draper and CED-6 are
scavenger receptor-like molecules essential for the clearance
of apoptotic cells in C. elegans and Drosophila (Liu and
Hengartner 1998; Zhou et al. 2001; Freeman et al. 2003). In
worms they are expressed in the phagocytic cell, whereas in
flies they are expressed in the glia. Mutations in ced-1/draper
inhibit clearance of the distal fragment of severed axons in
Drosophila olfactory receptor neurons (MacDonald et al.
2006). Similarly, in axons of the Drosophila mushroom
body, ced-1/draper and ced-6 are necessary for the clearance
of axonal fragments undergoing pruning (Awasaki et al.
2006). The finding that cell death genes such as ced-1 and
ced-6 are involved in the axonal degeneration process
suggests a partial commonality in the mechanisms, at least
in the later stages of these events, such as the removal of
axonal fragments or cell bodies after damage. The activation
of the glia and the function of these receptor molecules
indicate the existence of specific signals coming from the
damaged axon to which the glia are responding. Discovering
these cues is a key step towards understanding further how
axonal degeneration is triggered and achieved.
Mechanisms of axonal regeneration
Following axotomy, while the distal segment of the severed
axon undergoes Wallerian degeneration (Fig. 2a), the prox-
imal fragment attached to the cell body confronts two
potential fates: degenerate in a dying back fashion or
attempt to reconnect with its target by regeneration.
Successful axonal regeneration can be defined as the ability
of a severed axon to re-establish connectivity with its target.
This can happen through precise regrowth of the axon
(proximal fragment) from the injury site toward its target
following the original pathway (Fig. 2b), through regrowth
from the injury site toward its target along an ectopic
pathway (Fig. 2c), or through sprouting from an axonal
section far from the injury site along an ectopic pathway
(Fig. 2d). However, following nerve injury, functional
recovery can also occur through other mechanisms, for
example by sprouting from other non-damaged neurons
compensating for the loss of a neighboring tract, or by
plasticity of the system, with new contacts made among
surrounding neurons. An alternative mechanism of axonal
regeneration occurs in invertebrates (including the leech,
crayfish, and C. elegans), where the proximal regenerating
axon can directly contact its distal fragment, re-establishing
connectivity and preventing it from degenerating (Fig. 2e)
(Hoy et al. 1967; Carbonetto and Muller 1977; Deriemer
et al. 1983; Yanik et al. 2006).
In humans and other mammals, axonal regeneration occurs
in the PNS while it is reduced or absent in the CNS. In
zebrafish, some CNS neurons are able to regenerate while
others are not. Likewise, in C. elegans, with only 302
unmyelinated neurons, some axons regenerate after injury
whereas others do not. Axonal regeneration fails due to two
causes: a non-permissive external environment and neuronal
intrinsic factors. A large body of work in vertebrates has
revealed the crucial inhibitory role that the glia play in the
regenerative ability of a CNS axon following injury
(reviewed in Harel and Strittmatter 2006; Bradbury and
McMahon 2006; Yiu and He 2006). Several myelin-associated inhibitors have been discovered, including Nogo (a
member of the reticulon family) (Chen et al. 2000; GrandPre
et al. 2000; Prinjha et al. 2000), myelin-associated glycoprotein (McKerracher et al. 1994; Mukhopadhyay et al.
1994), oligodendrocyte myelin glycoprotein (Wang et al.
2002b), ephrin B3 (Benson et al. 2005), and the transmembrane semaphorin 4D/CD100 (Moreau-Fauvarque et al.
2003). Identified receptors for these molecules include Nogo
receptor (Fournier et al. 2001; Domeniconi et al. 2002; Liu
et al. 2002; Wang et al. 2002b), P75 (Wang et al. 2002c;
Wong et al. 2002; Yamashita et al. 2002; Domeniconi et al.
2005), TROY (Park et al. 2005; Shao et al. 2005), and
LINGO1 (LRR and Ig domain-containing, Nogo receptor
interacting protein) (Mi et al. 2004). An additional important
source of inhibition comes from the glial scar. Here, reactive
astrocytes, recruited to the site of injury, secrete inhibitory
extracellular matrix molecules such as chondroitin sulfate
proteoglycans. In these molecules, long unbranched glycosaminoglycan chains are attached to a proteic core, and
Ó 2008 The Author
Journal Compilation Ó 2008 International Society for Neurochemistry, J. Neurochem. (2009) 108, 23–32
Axonal degeneration and regeneration | 27
Fig. 2 Schematic illustration of axonal regeneration mechanisms.
After injury the distal fragment undergoes Wallerian degeneration (a).
The proximal fragment can regrow (b) from the site of injury toward its
target (neuron or muscle) along the same pathway where the distal
fragment lay, (c) from the site of injury along new alternative pathways,
or (d) through sprouting from an axonal section different from the site
of injury along an ectopic pathway. Alternatively, as observed in
Caenorhabditis elegans and other invertebrates, (e) the proximal
regenerating fragment can directly contact its distal fragment, reestablishing connectivity and preventing it from undergoing Wallerian
degeneration.
evidence exists that these play an important role in the
inhibition of axonal regeneration (reviewed in Silver and
Miller 2004; Carulli et al. 2005).
In addition to extracellular elements, numerous studies
have revealed the crucial role that neuronal intrinsic factors
play in determining the regenerative ability of a neuron. An
example of this lies in the inability of some injured axons to
regrow even if placed in a permissive environment.
Important findings have shown that pre-conditioning nerve
lesions generated days in advance can influence and
enhance the regenerative potential of a subsequent lesion
of the same nerve (McQuarrie and Grafstein 1973). Similar
results have been obtained more recently in mice, using
neurons of the dorsal root ganglia (DRG). These neurons
present two branches coming out of the unipolar axon, a
peripheral branch that can regenerate and a second branch
that enters the CNS and is unable to regenerate. Pre-
conditioning lesions on the PNS side of the DRG axons can
have a strong enhancing effect on the regenerative ability of
the CNS side of these axons, allowing regeneration into and
beyond the lesion site (Neumann and Woolf 1999). Thus,
the pre-conditioning lesions are able to enhance the intrinsic
growing capacity of these neurons. One mechanism underlying the increased axonal regrowth appears to be based on
cAMP levels. In fact, similar results of increased axonal
regrowth can be mimicked with pre-treatment of the DRG
neurons with a membrane-permeable cAMP analog (dibutyryl cAMP; db-cAMP), which elevates the intracellular
concentration of cAMP in these cells (Neumann et al.
2002). In addition, peripheral lesion or incubation with dbcAMP enables neurites to grow on inhibitory substrates
(Neumann et al. 2002). These results have been extended
further in zebrafish, based on a model using the Mauthner
cells (M cells), the myelinated neurons necessary for escape
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28 | M. A. Hilliard
behavior (Bhatt et al. 2004). The axon of the M cell
regenerates poorly after spinal lesion, although other
neurons in the nerve cord are able to regenerate, indicating
the permissive environment of this tissue. In this case,
application of db-cAMP directly onto the somata of the M
cells 3–5 days after the lesion allows axonal regeneration
through and beyond the injury site (Bhatt et al. 2004).
Thus, a cell-intrinsic mechanism can change the growthstate of neurons and provide them with an acquired ability
to overcome inhibitory stimuli.
Additional evidence on the important role that neuronal
intrinsic factors play in axonal regeneration comes from
studies of brainstem neurons in chick. Changes within
maturing brainstem neurons dramatically reduce their ability
to regenerate their axons, even into a young spinal cord that
allows abundant axonal regeneration from young brainstem
neurons (Blackmore and Letourneau 2006a). L1/neuron–glia
cell adhesion molecule, b1 integrin, and cadherins are crucial
elements for axonal regeneration in these neurons as
simultaneous blockage of these molecules reduces the axonal
growth of embryonic neurons by 90% (Blackmore and
Letourneau 2006a,b).
An important aspect in the understanding of such an active
process as axonal regeneration is the identification of the
dynamic events taking place at the injury site. Recent
improvements of in vivo imaging following nerve injury have
allowed this issue to be addressed, revealing key details of
the precise dynamics of axonal degeneration and regeneration in the CNS (Bareyre et al. 2005; Kerschensteiner et al.
2005). Kerschensteiner et al. have used a transgenic strain
of mice expressing green fluorescent protein in a subset
of neurons, including those of the DRG. In this system,
individual DRG axons in the spinal cord are monitored
immediately after injury (induced with a small needle) and
over the following several hours. In the first half an hour, the
proximal and distal axonal fragments undergo a symmetrical
acute degeneration phase, which causes them to separate
(300 lm). The acute axonal degeneration is responsible for
almost 90% of the total axonal loss occurring in the first 4 h
after injury. The symmetry of this degeneration is very
relevant because it eliminates part of the axon (proximal) that
is still linked to the cell body, including branches if present.
The onset of proper Wallerian degeneration of the distal
segment takes place between 1 and 2 days after injury.
Interestingly, in the first 2 days 30% of the proximal
segments show active and rapid regeneration, in some cases
starting as early as 6 h after injury. However, these sprouts
grow in different directions without getting substantially
closer to their targets, possibly because they lack correct
guidance cues. These results support the idea that some adult
neurons in the CNS possess an intrinsic potential to
regenerate in vivo.
In a much simpler scenario of axonal regeneration, as
observed in C. elegans (see below), the proximal segment of
a severed axon would regrow, reconnecting with its distal
fragment. This would prevent it from degenerating and lead
to the recovery of neuronal function. For this to occur, the
regenerating fragment would need to reach the distal
fragment in a timely manner before Wallerian degeneration
irreversibly takes place. However, earlier studies in mice
have shown that axonal regeneration in PNS motor and
sensory neurons is delayed in WldS mutants compared with
wild-type animals (Bisby and Chen 1990; Brown et al. 1992,
1994). In the proposed model, axonal regeneration is
impaired when Wallerian degeneration does not follow its
normal time course after injury. From this perspective,
degeneration of the distal stump would enhance the active
regrowth of the proximal segment into the damaged area. A
delicate balance must be in place to ensure a certain degree of
degeneration that allows functional regrowth in the PNS.
This hypothesis is supported by the fact that multiple lesions
along the nerve stump increase the axonal regeneration rate
(Brown et al. 1994). However, this is a less intensely
explored field and it would be interesting to see if, in light of
these new findings, it is also possible to enhance functional
axonal regeneration in a more intact tissue protected from
degeneration.
Recent technical advances have now made it feasible to
study axonal regeneration in genetically tractable organisms
such as C. elegans (Yanik et al. 2004). In worms, a laser
microbeam can be used to snip individual axons of green
fluorescent protein-labeled neurons, and the axonal regeneration pattern can be observed. Despite the absence of
myelin, the restricted number of glial cells (about 50), and
the overall simplicity of the system, some axons do
regenerate whereas others do not (Yanik et al. 2004, 2006;
Wu et al. 2007; Gabel et al. 2008). These differences offer
enormous opportunities to understand how neuronal intrinsic
regenerative potential is established. In C. elegans, when
individual processes of the anterior and posterior lateral
mechanosensory neurons (ALM and PLM respectively) are
axotomized, their proximal fragments will regrow toward
their distal fragments. If the regenerating proximal axon
makes contact with the distal fragment, the distal fragment is
protected and survives; otherwise it invariably undergoes
Wallerian degeneration (Yanik et al. 2006). In this case, time
is of the essence to shift the balance toward a fully
successful regeneration rather than towards a degenerative
condition. Developmental stage affects axonal regeneration,
with older animals being less successful in regenerating their
neuronal processes (Wu et al. 2007). Using a candidate gene
approach and the posterior lateral mechanosensory neuron
as a model, Wu et al. have shown that ephrin signals
influence the guidance of regrowing axons. In ephrin or Eph
receptor mutants, the regenerating axonal process grows
straighter than in wild-type animals. In a similar set of
experiments using a different anterior ventral mechanosensory neuron (AVM), Gabel et al. (2008) have shown that
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Axonal degeneration and regeneration | 29
MIG-10/Lamellipodin, UNC-34/Enabled, and CED-10/Rac
are necessary for correct axonal regrowth.
It appears that C. elegans genetics has not yet attained its
full power in this field, one reason being the time-consuming
surgery step (about 10 min/animal). Recent engineering
applications, based on the development of microfluidic
devices designed to trap one or more individual worms into
small chambers, have addressed this issue and reduced by a
factor of 10 the time required for the surgery (Guo et al.
2008). Importantly, these novel tools allow immobilization of
the worm without the use of anesthetics. This has already
revealed the interesting finding that the regeneration process
occurs on a much faster time scale (in the first hour after
surgery) than previously thought, and that the distal fragment
of a severed axon is also able to undergo active regrowth (Guo
et al. 2008). These essential technical advances mean unbiased genetic screens and pharmacological screens are now a
realistic possibility (Rohde et al. 2007; Guo et al. 2008).
Another recent important discovery is the identification
and characterization of a C. elegans mutant strain with a
defect in the gene unc-70, encoding for b-spectrin (Hammarlund et al. 2000, 2007; Moorthy et al. 2000). b-Spectrin
forms part of the membrane skeleton of most cells, including
neurons (Bennett and Baines 2001). In unc-70 mutants, the
axons of the GABAergic motor neurons continuously break
and attempt to regenerate (Hammarlund et al. 2007). These
animals therefore provide an excellent genetic tool to study
axonal degeneration and regeneration in great detail.
It is foreseeable that in the coming years new essential
molecules and mechanisms involved in these crucial processes will be discovered, possibly contributing to the
development of more effective therapies.
Conclusion
Like two sides of the same coin, axonal degeneration and
regeneration are crucial processes regulating normal development as well as pathological conditions of the nervous
system. We have acquired some knowledge of the neuronal
intrinsic and extrinsic factors underlying axonal degeneration
and regeneration as distinct processes, although we are just
starting to understand how they are connected and how they
can influence each other. In some cases, as in vertebrates, a
certain level of degeneration appears to be necessary for
axonal regeneration to occur; in other cases, as in invertebrates, successful axonal regeneration seems independent of
degeneration or even functionally improved if degeneration
does not take place. Research aimed at understanding the
molecular and cellular basis underlying these mechanistic
differences might reveal important elements necessary for the
development of more effective therapies for neurodegenerative conditions and nerve injuries. The substantial improvement of imaging techniques to visualize these dynamic
processes in higher organisms, together with the development
of genetic animal model systems suitable to address these
biological questions, are now providing high hopes that key
discoveries will occur in this frontier field of neurobiology.
Acknowledgements
The author would like to thank Paolo Bazzicalupo, Rowan
Tweedale, Brent Neumann, Leonie Kirszenblat, Adela Ben-Yakar,
and Frederic Bourgeois for critical discussion and helpful comments
on the manuscript, Ian Glidden for his help in designing the figures,
and the three anonymous reviewers for their insightful comments.
The author would also like to apologize to those authors whose
work could not be cited because of space limitations. This work was
supported by a NIH R01 Grant NS060129-01.
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