What is axonal degeneration

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However, altering physiological conditions up to a few hours after injury, such as by lowering ambient temperature and reducing extracellular calcium levels or by genetically expressing the WldS transgene, significantly prolongs the latency period, during which the injured axons remain in a vulnerable but functional state George et al.

Therefore, identifying the underlying molecular events during the different morphological phases may reveal specific targets to delay or even rescue axon degeneration. It was previously thought that transected axons are structurally dormant from the time of injury until the onset of axonal fragmentation.

However, recent in vivo real-time imaging studies reveal that the injured axons are far more dynamic shortly after injury. As soon as a few minutes after axotomy, the axonal segments immediately proximal and distal to the injury site rapidly degenerate by several hundred micrometers in either direction in a process that lasts between 5 and 60 min Kerschensteiner et al.

This early response to injury is followed by a slower formation of dystrophic bulb structures at the terminals of both transected ends due to accumulation of axoplasmic organelles from ongoing anterograde and retrograde transport Fig.

The short, early-onset degenerative event, termed acute axonal degeneration AAD , has been observed in both dorsal spinal sensory and optic nerves in vivo Kerschensteiner et al. Increased calpain cleavage of spectrin occurs as early as 30 min after injury in vivo Kampfl et al.

However, chemical inhibition of calpain fully abrogates this short distance degeneration at the severed ends of spinal cord axons Kerschensteiner et al. What is the purpose of AAD, and does it contribute to subsequent Wallerian degeneration of the entire distal axon?

Earlier studies suggest that calpain-mediated proteolysis of neurofilaments aid in cytoskeletal restructuring and formation of growth cones in regenerating axons Spira et al. Furthermore, the space created by this short-distance axon degeneration may enable glial proliferation at the lesion site and provide a more permissive environment for regeneration of the proximal axon.

Thus, AAD may be the principal mechanism by which injured proximal axons are lost to allow neurite regrowth. However, whether AAD affects degeneration of the distal axonal segment is less clear. In contrast to the proximal stump, which begins to produce axoplasmic sprouts toward the lesion site only a few hours after axotomy Kerschensteiner et al.

For instance, severed axons of motor neurons retain their ability to conduct action potentials up to 24 h after injury in vivo, though the evoked potentials and conduction velocity progressively decay Moldovan et al. Additionally, both anterograde and retrograde transport activities continue in the distal axon Smith and Bisby, What is the molecular basis of this physiological latency in the injured axon, and more importantly what triggers the abrupt transition from this phase to rapid, irreversible physical degeneration?

We examine the molecular events that have been shown to modulate the duration of axon survival, and discuss their roles as potential triggers for the switch to axonal degradation. What are the major causes of elevated intra-axonal calcium after traumatic nerve injury?

Indeed, it was previously shown that L-type, but not N-type calcium channel blockers significantly delay axon degeneration for 4 d after axotomy George et al. Recent evidence suggests that the latter is more likely to be the case. Events similar to Wallerian axon degeneration also occur in genetic mutants such as pmn that are impaired in axonal transport Martin et al. Two potential mechanisms may be used by the cell to signal nerve injury and initiate axon degeneration.

There is recent evidence supporting both hypotheses. For instance, loss-of-function mutations in mammalian DLK or its Drosophila homologue wallenda , a member of the mitogen-activated kinase kinase kinase family, as well as use of a chemical inhibitor of JNK kinase, a target of DLK, all result in axon protection up to 48 h after axotomy Miller et al.

In all these events, the axonal protection occurs only when the kinase activity is inhibited between time of axotomy and up to 3 h after injury Miller et al. Yet it is unclear how injury leads to activation of these kinases, and whether increased kinase activity is sufficient to induce spontaneous axon degeneration or abolish WldS-mediated axon protection.

In another study supporting the presence of an axonal self-destruction signal, Nikolaev et al. However, blocking the release of APP or chemically inhibiting caspase-6 fails to delay axon degeneration after axotomy Vohra et al.

At the same time, there is also evidence suggesting that a constitutively transported or expressed factor normally supports axonal survival, and its absence or degradation after injury triggers axon degeneration. Recently, Gilley and Coleman observed that focal inhibition of protein translation in the cell body, but not in the axon, results in spontaneous axon degeneration of uninjured neurites. This suggests that synthesis of a protein factor in the soma and its delivery to the axon, rather than local axonal translation, maintains axon viability.

It is expressed in the axons and its expression quickly decreases within 4 h after axotomy or after blockade of axonal transport Gilley and Coleman, This turnover time for the protein correlates with the latent period between axon injury and the initial appearance of axonal blebbing Beirowski et al. Moreover, depletion of Nmnat2, but not other isoforms of Nmnat enzyme using siRNA specifically induces degeneration in uninjured axons, while overexpression of Nmnat2 delays the degeneration of wild-type axons from axotomy for up to 48 h Gilley and Coleman, ; Yan et al.

These exciting findings indicate that Nmnat2 is continuously required to promote endogenous axon survival, and that decreased level of the protein—caused by impaired axonal transport from the soma, local degradation in the axon, or both—leads to failure to suppress a default axon degeneration program Fig. Previous studies demonstrate that inhibiting the ubiquitin—proteasome system UPS by blocking proteasome activity prevents axon pruning during development Watts et al.

How does proteasome inhibition protect axons, and through what mechanism does axonal injury affect ubiquitination or proteasome activity? As the primary function of the proteasome is to regulate protein turnover, a likely explanation is that proteasome inhibition helps sustain intracellular levels of molecules that promote axonal survival by maintaining transport of the factor to the axon or by preventing the degradation of the molecule itself.

Consistent with the first mechanism, proteasome inhibition in axotomized nerves attenuates microtubule disassembly and preserves axonal transport by preventing the turnover of microtubule-associated factors such as MAP1 and tau that help stabilize the microtubule network Zhai et al. Moreover, inhibiting proteasome activity may also directly interfere with the degradation of a putative axonal survival factor such as Nmnat2.

Indeed, the turnover of Nmnat2 is shown to be dependent on proteasome activity as its levels in the transected axon remain high when proteasome activity is blocked Gilley and Coleman, Thus, in axonal injuries where the somal supply of the factor is lost, the level of the survival factor in the axon is then solely determined by its rate of proteasome-dependent degradation, whereas proteasome inhibition helps sustain sufficient levels of the factor in the axon to delay the onset of axon degeneration Fig.

Interestingly, focal, severe injuries such as axotomy result in a proximal-to-distal direction of axon degeneration, whereas in more chronic injuries the axons degenerate from synaptic ends to the cell body in a retrograde pattern Beirowski et al. The basis for the injury-dependent differences in the direction of degeneration is not fully understood. However, whether this mechanism participates in Wallerian degeneration and whether the signaling events occur broadly in other CNS neurons is unclear.

The segment closest to the cut site would likely experience the earliest loss of the survival factor, and therefore be the first to undergo degeneration after axotomy. The discovery of the WldS mouse mutant, which robustly protects both CNS and PNS nerves from physical injury, chemotoxic insult, and neurodegenerative conditions Lunn et al. In contrast to complete fragmentation of wild-type axons within 48 h after axotomy, the transected WldS axons remain structurally intact and electrically excitable for weeks in vivo and up to a week in culture Lunn et al.

Transgenic expression of the WldS protein also leads to axon protection in many species, including rats Adalbert et al. This protection, which is dose dependent Mack et al.

Continued axon protection after grafting WldS nerves to wild-type hosts shows that WldS-mediated protection is intrinsic to the axon Glass et al. Thus, determining the molecular components of the degeneration pathway that WldS is interfering with is critical to understanding how axons are normally lost after injury.

However, overexpression of mutant Nmnat that lacks the enzymatic domain in Drosophila still protects photoreceptor cells from SCA-1—induced degeneration Zhai et al. This nonenzymatic protection by Nmnat has been shown to be a consequence of chaperone functions of the protein Zhai et al.

However, whether this phenotype is axonal specific or an indirect result of broader protection of the cell bodies remains unclear. Although the WldS protein is predominantly localized in the nucleus due to endogenous nuclear localization of Nmnat1, emerging evidence instead points to the trace amount of extranuclear WldS protein as the critical component for axon protection Coleman and Freeman, Indeed, WldS protein has recently been detected in the axoplasm and in axonal organelles including the mitochondria and phagosomes Beirowski et al.

Moreover, misexpression of Nmnat1 alone outside of the nucleus by deleting its nuclear localizing sequence Beirowski et al. Although one cannot rule out the additional contribution of gene changes caused by WldS expression Gillingwater et al. How does the WldS protein mediate axon protection, and where does this activity intersect with the normal degenerative process?

And as endogenous Nmnat2 activity is essential for axonal survival, it is suggested that the WldS protein protects axons by augmenting or substituting for Nmnat2 to maintain sufficient levels of Nmnat enzyme activity in the distal axons after injury Gilley and Coleman, Consistent with this hypothesis, in vivo tracing of GFP-tagged WldS protein in uninjured nerves shows that WldS is normally present in axonal regions where Nmnat2 is also expressed. Moreover, Nmnat2 is found to rapidly degrade, even in WldS nerves, within 4 h after nerve injury, whereas the WldS protein remains stable in the distal axon Gilley and Coleman, These reports strongly argue that a molecular mechanism by which the WldS protein confers axon protection is by sustaining key levels of Nmnat activity in the axon that would normally diminish from decreasing Nmnat2 expression after injury Fig.

Moreover, as additional Nmnat isoforms exist in different subcellular regions, WldS protein may also promote axonal survival by augmenting the activity of other Nmnat enzymes. Consistent with this, overexpression of Nmnat3, a mitochondrial Nmnat isoform Berger et al. Although Nmnat3 is not required for normal maintenance of axonal survival Gilley and Coleman, , its overexpression results in significantly stronger axonal protection than from overexpression of Nmnat2, though this may be due to the labile nature of Nmnat2 protein Gilley and Coleman, As the WldS protein is also identified in the mitochondria Yahata et al.

Assessing whether expression of WldS continues to protect axons in Nmnat2 or Nmnat3 knockouts will help reveal the critical site of Nmnat activity for conferring axonal protection. Yet, precisely how increased Nmnat enzymatic activity in WldS, Nmnat2, or Nmnat3 protects the axons remains a mystery.

However, Press and Milbrandt recently reported that increasing mitochondrial Nmnat3 activity is sufficient to delay axon degeneration even from rotenone, a blocker of mitochondrial oxidative phosphorylation. This axonal protection is independent of ATP levels as the rate of ATP loss is similar between Nmnat3-expressing and wild-type axons treated with rotenone Press and Milbrandt, However, how each molecular component interacts to orchestrate the initiation and execution of axonal self-destruction after injury is unclear.

These changes result in the progressive disintegration of the axon and myelin. Fragments of the axon often contain large amounts of myelin debris and are called myelin ovoid. Schwarmcells proliferate and ingest the degenerating axon.

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