Caspases in Wallerian Degeneration

Before the observations that UPS was involved in the initial stages of wallerian degeneration, an attractive hypothesis was that members of the apoptotic pathway might be regulating or executing the axonal degeneration seen after injury akin to the apoptosis of injured cells. Similar to wal-lerian degeneration, apoptosis in the nervous system is an active process that requires energy and presence of regulatory proteins and enzymes capable of degrading cellular proteins (Yuan and Yankner, 2000). The final stages of apop-tosis involve activation of caspases, the executioners of apoptosis, which then lead to degradation of cellular proteins and nuclear DNA (Hengartner, 2000). Because cas-pases are capable of protein degradation and their activities are tightly controlled, activated caspases could have been an ideal candidate as executers of wallerian degeneration; however, two lines of evidence argue against a strong role for caspases in wallerian degeneration. Raff and colleagues examined the role of caspase-3 in wallerian degeneration (Finn et al., 2000). At a time when caspase-3 was activated in the cell body, there were no activated caspase-3 or cleaved substrates of caspase-3 in the distal segment of a nerve after transection. Furthermore, inhibitors of the caspase pathway did not prevent wallerian degeneration, yet they prevented apoptosis of the cell body. In a second study, Raff and colleagues examined the events upstream of caspase activation (Whitmore et al., 2003). They used the optic nerve transec-tion as a model to study the relationship between the apop-totic processes and wallerian degeneration. When the optic nerve was transected, retinal ganglion cell neurons underwent apoptotic cell death. This was prevented in double knock-out animals lacking two of the key proapoptotic proteins Bax and Bak. Yet there was no difference in the waller-ian degeneration of the transected optic nerve axons in

Figure 3 Proposed role of the ubiquitln-proteasome system (UPS) in wallerian degeneration. (A) Axonal injury or insult leads to fragmentation of the microtubule and neurofilament cytoskeleton followed by disintegration of the axon. Preventing polyubiquitination or proteasome-mediated degradation delays cytoskeletal fragmentation and degeneration. (B) Although the precise mechanisms are unknown (indicated by question marks), axonal degeneration requires Ca2+ influx, which leads to activation of intracellular proteases such as cal-pain and possibly ubiquitin (Ub)-regulatory enzymes, including E3 and E4 ubiquitin ligases. Disassembly of microtubules could proceed by ubiquitination and degradation of stabilizing microtubule-associated proteins (MAPs). Degradation of neurofilaments might be due to a combination of calpain-mediated and UPS-mediated degradation. (With permission from Ehlers, 2004.)

Axon transection

Soma

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Cytoskeletal fragmentation

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Proteasome inhibited

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TRENDS in Neurosciences

Bax-~/Bak-~ animals compared to the wild-type animals. The results were similar in the distal segment of the transected sciatic nerve. Taken together, these results argue strongly against a pivotal role for members of the apoptotic pathway in wallerian degeneration.

In another study examining the role of apoptotic machinery in wallerian degeneration, Ikegami and Koike (2003) studied the mitochondrial function in vinblastine-induced neuronal death and axonal degeneration. They found that although vinblastine caused apoptotic death of the neuron, the axonal degeneration that preceded the cell death was not mediated by the classical apoptotic machinery; there was no activated caspase-3 in the degenerating axons, and axonal degeneration was not prevented by caspase-3 inhibitors. Yet there was a significant mitochondrial dysfunction in the axon, with loss of the mitochondrial membrane potential and loss of adenosine triphosphate synthesis before the morphological evidence of axonal degeneration. This idea that local mitochondrial dysfunction can lead to axonal degeneration is gaining momentum, although most of the evidence is indirect and circumstantial. In patients infected with the human immunodeficiency virus-1 (HIV-1), the incidence of neuropathy with distal axonal degeneration increases with the use of nucleoside reverse transcriptase inhibitors. In a detailed study of HIV-infected patients with peripheral neuropathy who are receiving nucleoside reverse transcriptase inhibitors, Dalakas and colleagues (2001) showed that there are alterations in the axonal mitochondrial morphology and accumulation of mitochondrial mutations. There is an increasing body of evidence suggesting that persistent hyperglycemia may lead to mitochondrial dysfunction and apoptotic cell death in tissue culture and animal models of diabetic neuropathy (Russell et al., 1999; Srinivasan et al., 2000; Schmeichel et al., 2003). It is likely that localized mitochondrial dysfunction may also lead to axonal degeneration before any evidence of cell death occurs. However, this remains speculative at this moment, as there is no firm experimental evidence.

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