Degeneration and regeneration of the nervous system

ALS: a disease of motor neurons and their nonneuronal neighbors.

Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth.

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

The cellular and molecular basis of peripheral nerve regeneration.

https://www.cell.com/neuron/pdf/0896-6273(94)90042-6.pdf

A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration

Wallerian degeneration of the distal stump of a severed peripheral nerve involves invasion by myelomonocytic cells, whose presence is necessary for destruction of myelin and for initiating mitosis in Schwann cells (Beuche and Friede, 1984). Degeneration of the distal ends of the axons themselves is assumed to occur by autolytic mechanisms. We describe a strain of mice (C57BL/6/Ola) in which leucocyte invasion is slow and sparse. In these mice, confirming Beuche and Friede, myelin removal is extremely slow. A new finding is that axon degeneration is also very slow. This is a consequence of lack of recruitment of myelomonocytic cells for if such recruitment is prevented in other mouse strains by a monoclonal antibody against the complement type 3 receptor (Rosen and Gordon, 1987) axon degeneration is again slowed. We have also, surprisingly, found that nerve regeneration in the C57BL/6/Ola mice is not impeded by the presence of largely intact axons in the distal stump and absence of recruited cells, myelin debris and the absence of Schwann cell mitosis.

Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve.

We have described a mutant mouse, C57BL/Ola, in which Wallerian degeneration following peripheral nerve transection is very slow. Our previous results suggested that recruited monocytes play a role in rapid Wallerian degeneration. The nature of the mutation in C57BL/Ola mice is not known and we have investigated whether the defect is intrinsic to the nerve or due to a defect in the circulating monocytes. We have made chimaeric mice in which bone marrow from histocompatible mice, with rapidly degenerating nerves and normal monocyte recruitment, was used to reconstitute irradiated C57BL/Ola mice and vice-versa. A substantial degree of donor repopulation of the hosts was confirmed by measures of the levels of glucose-phosphate isomerase alloenzymes in blood and tissue samples from the two different strains. The rate of degeneration of the transected sciatic nerve was found to be host-dependent, providing evidence that the mutation affects cell populations intrinsic to the nerve and not the circulating monocytes. We provide additional evidence that the peripheral nerves of C57BL/Ola mice are different from those of other mice as they degenerate at a slower rate in vitro.

Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve.

Wallerian degeneration following peripheral nerve transection in C57BL/Ola mice is very slow in comparison to other strains of mice. We show that following optic nerve transection, the axons of retinal ganglion cells in C57BL/Ola mice undergo very slow Wallerian degeneration and that retrograde degeneration of the ganglion cell bodies is much slower than in other strains of mice. The results suggest that the gene product affecting Wallerian degeneration in the peripheral nervous system (PNS) also confers a greater resistance to degeneration on central nervous system (CNS) neurons.

Very Slow Retrograde and Wallerian Degeneration in the CNS of C57BL/Ola Mice.

In a substrain of C57BL mice, C57BL/Ola, Wallerian degeneration in the distal segment of the severed sciatic nerve is extremely slow when compared to other mice. Despite this very slow degeneration in the distal segment regeneration of the motor nerves is not impaired. From suitable genetic outcrosses and backcrosses, the authors provide evidence that the rate of Wallerian degeneration in this strain is controlled by a single autosomal gene product. The authors have also shown that the rate of degeneration, in C57BL/Ola mice, is influenced by the environment in which the animals were bred and housed. Wallerian degeneration in the sciatic nerves of mice raised in isolators is slower than in those raised in a conventional animal house. This strain of mouse may prove to be of value in the understanding of nerve degeneration and regeneration.

/pdf/evidence-that-the-rate-of-wallerian-degeneration-is-4rawthv22r.pdf

Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene.

The time course of Wallerian degeneration in the tibial and saphenous nerves was compared in Balb/c mice and mice of the C57BL/Ola strain (Lunn et al., 1989). Axons, particularly myelinated ones, in nerves of C57BL/Ola mice are very slow to degenerate, many still being present 3 weeks after axotomy. Nuclear numbers in the distal stump peak much later and do not reach the levels found in Balb/c mice; debris removal is very slow, and Schwann cell numbers only rise slightly above normal levels in the long term. Regeneration was investigated electrophysiologically and by electron microscopy (EM). Myelinated sensory axons regenerated slowly and incompletely compared with motor ones which were only slightly slowed after nerve crush (although they were significantly hindered after nerve section). Total myelinated axon numbers were still some 20% less than normal even after 200 days in sensory nerves. Even after all axons had degenerated in C57BL/Ola mice, regeneration rates of neither myelinated nor unmyelinated sensory axons reached those achieved in Balb/c mice. It is concluded that while regeneration can eventually proceed slowly when Wallerian degeneration is much delayed, the usual rapid time course of Wallerian degeneration is necessary if axons, particularly sensory ones, are to regenerate at optimal rates and to maximum extent. While local obstruction to axon growth probably impedes the early phase of regeneration in C57BL/Ola mice, it seems possible that a lack of adequate early signals affects regeneration permanently by minimizing the cell body reaction to injury.

E. R. Lunn

Papers

Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve.

Evidence that Very Slow Wallerian Degeneration in C57BL/Ola Mice is an Intrinsic Property of the Peripheral Nerve.

Very Slow Retrograde and Wallerian Degeneration in the CNS of C57BL/Ola Mice.

Evidence that the Rate of Wallerian Degeneration is Controlled by a Single Autosomal Dominant Gene.

Consequences of slow Wallerian degeneration for regenerating motor and sensory axons.