Compartmental neurodegeneration and synaptic plasticity in the Wld^s mutant mouse

Abstract

Orthograde degeneration in the distal segment of severed axons was first described by Augustus Waller in 1850, when he examined lesioned hypoglossal and glossopharyngeal nerves in the frog. Waller noted that the axon disintegrated and the remaining debris was subsequently removed within a few days of axotomy. However, our present knowledge and understanding of the underlying mechanisms of Wallerian degeneration (WD) remain sketchy, despite the advent and improvement of physiological, immunocytochemical and molecular techniques.Our aim here is fourfold. First, to briefly review what is known about WD in wild-type animals. Second, to discuss the characteristic phenotype of the spontaneous mutant Wld s mouse, and the opportunities this mutant offers to gain insights into the molecular mechanisms of WD. Third, to appraise the evidence that WD is one of several distinctive, compartmentalised degeneration mechanisms in neurones, whereby survival of cell bodies and dendrites, axons, and synaptic terminals may be regulated independently. Finally, we argue for the utility of the Wld s mouse as a paradigm for studying other issues in neurobiology, such as mechanisms responsible for plasticity of synaptic structure and function.(1) Wallerian degeneration of axons and motor nerve terminals Axons. The primary event in WD is axonal fragmentation and degeneration (Vial, 1958;Allt, 1976;Hallpike, 1976;Nicholls et al. 1992). Subsequent breakdown and removal of the myelin sheath occurs by phagocytosis involving the invasion of myelomonocytic cells after the onset of axonal degeneration (Beuche & Friede, 1984). Once the lesioned axon has begun to fragment, the myelin sheath retracts from the nodes of Ranvier creating enlarged nodal spaces (Fig. 1). These then segregate the nerve into 'digestive chambers' or 'ellipsoids ' (Allt, 1976). Within each of these compartments, the axon fragments proceed to a state of complete degradation. Electron microscopy has demonstrated that the major early axonal changes include fragmentation of endoplasmic reticulum and dissolution of neurofilaments and microtubules within 48 h (Vial, 1958;Honjin et al. 1959;Ballin & Thomas, 1969;Donat & Wisniewski, 1973). These changes have been attributed by Schlaepfer (1974) to the influx of calcium ions at the lesion site. Soon after the onset of these events it is also possible to detect a more distinctive degenerative marker, the swelling and lysis of axonal mitochondria.As degradation of the axon continues, the ellipsoids are removed by phagocytosing Schwann cells and invading macrophages. At the same time, Schwann cells proliferate: in lesioned rabbit sciatic nerve after 25 days there are up to 13 times the number present before injury (Abercrombie & Johnson, 1946). These Schwann cells join together, tip to tip, forming longitudinal bands known as 'bands of Büngner'. The Schwann cell bands may play a role in guiding the regenerating proximal nerve stump axons back to the denervated site. Schwann cells secrete many different growth and adhesive factors such ...

Reinnervation of the tibialis anterior following sciatic nerve crush injury: A confocal microscopic study in transgenic mice

“…Denervation is also demonstrated at this time point by some axons making distal contact with endplates, but lacking proximal continuity. The presence of incongruent distally-intact terminal axons contacting their endplates likely illustrates the "compartmental" theory of (Fig 1B-C) neurodegeneration, in that the neuronal soma, projecting axon, and synaptic terminal axon all degenerate via separate and distinct processes (Araki, et al, 2004,Gillingwater and Ribchester, 2001,Gillingwater and Ribchester, 2003. By two weeks, some continuous axons are seen, suggesting that concomitant regeneration and degeneration take place at this time point.…”

Neuroprotection after Transient Global Cerebral Ischemia in Wlds Mutant Mice

“…The inclusion of a fragment of an E4 ubiquitination factor, Ube4b, in the Wld gene suggests that a mechanism involving altered ubiquitination of proteins may underlie the protective role of Wld (Coleman and Perry, 2002;Gillingwater and Ribchester, 2001;Mack et al, 2001). After transient cerebral ischemia, impairment of protein ubiquitination occurs (Magnusson and Wieloch, 1989).…”

Dysmyelinated Lower Motor Neurons Retract and Regenerate Dysfunctional Synaptic Terminals

“…Mechanisms of neuronal degeneration are highly compartmentalized (Gillingwater and Ribchester, 2001). Injury or deprivation of growth factors can lead to apoptotic death of the neuronal cell body, followed by rapid degeneration of dendrites, axons, and synaptic terminals (Pettmann and Henderson, 1998).…”