Wallerian Degeneration Is an Active Process

Waller's initial observation, more than 150 years ago, that the distal stumps of transected nerve fibers degenerate (Waller, 1850), and subsequent findings that most proteins in the axon are synthesized in the cell body and transported down the axons using specialized transport mechanisms led to the attractive hypothesis that degeneration of the distal stump of a transected axon occurs because of lack of necessary proteins and other materials. However, slowed waller-ian degeneration observed in a strain of mice (C57Bl/Ola, now called Wlds for wallerian-like degeneration slow) changed that perception dramatically (Lunn et al., 1989; Perry et al., 1990; Glass and Griffin, 1991). In this spontaneously generated strain, degeneration of the transected axons is slowed significantly (Fig. 2). In a wild-type animal, transection of the sciatic nerve results in loss of electrical conductivity in the distal portion within a day or two, followed by dissolution of the axoplasm. In contrast, a transected axon in a Wlds mouse continues to conduct electricity for up to 2 weeks (Lunn et al., 1990; Tsao et al., 1994). This delayed process suggests that wallerian degeneration is an active process that requires the presence and activation of a cellular pathway that regulates the dissolution of the axo-plasm. This cellular pathway is similar to the pathway that

(C) Wlds transgenic

(C) Wlds transgenic

Ube4b Nmnat

Figure 2 Axon protection in mice expressing the chimeric Wlds gene. Ultrathin transverse sections of (A) wild-type, (B) Wlds, and (C) transgenic Wlds sciatic nerve distal to a site of transection 14 days after the lesion. (D) Wlds chimeric protein and its parent proteins (drawn to scale) in these strains. The proteins below (B) and (C) are those produced in both Wlds and Wlds-transgenic mice. Two copies of the chimeric protein are shown to indicate that there are two copies of the chimeric gene per haploid genome. Abbreviations: Nmnat, nicoti-namide mononucleotide adenylyltransferase; Ube4b, ubiquitination factor E4B. Scale bar, 10 |m. (With permission from Coleman and Perry, 2002.)

Ube4b Nmnat

Chimeric protein

Figure 2 Axon protection in mice expressing the chimeric Wlds gene. Ultrathin transverse sections of (A) wild-type, (B) Wlds, and (C) transgenic Wlds sciatic nerve distal to a site of transection 14 days after the lesion. (D) Wlds chimeric protein and its parent proteins (drawn to scale) in these strains. The proteins below (B) and (C) are those produced in both Wlds and Wlds-transgenic mice. Two copies of the chimeric protein are shown to indicate that there are two copies of the chimeric gene per haploid genome. Abbreviations: Nmnat, nicoti-namide mononucleotide adenylyltransferase; Ube4b, ubiquitination factor E4B. Scale bar, 10 |m. (With permission from Coleman and Perry, 2002.)

regulates apoptotic cell death in the sense that both are regulated active processes requiring energy, but there are significant differences as well. The molecular characters that play a role in this active self-destruct mechanism are not well understood, but are different from those involved in apoptosis (see later).

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