Nogo and axon regeneration

https://doi.org/10.1016/j.conb.2004.01.004Get rights and content

Abstract

Nogo-A is one of several neurite growth inhibitory components present in oligodendrocytes and CNS myelin membranes. Nogo has a crucial role in restricting axonal regeneration and compensatory fibre growth in the injured adult mammalian CNS. Recent studies have shown that in vivo applications of Nogo neutralizing antibodies, peptides blocking the Nogo receptor subunit NgR, or blockers of the postreceptor components Rho-A and ROCK induce long-distance axonal regeneration and compensatory sprouting, accompanied by an impressive enhancement of functional recovery, in the rat and mouse spinal cord.

Introduction

“The lame shall walk.” (Matthew chapter 11, verse 5)

Paraplegia has been a model of human suffering since ancient times. The crucial medical issues are management of the paralysed bladder, prevention of decubitus and wound infections, assuring respiration for individuals with high-level injuries, stabilizing the spinal column, and finally training for a life in a wheelchair. Traditionally, neurology has had almost no role in this field: spinal cord damage has been considered to be incurable and out of the reach of medical intervention.

Over the past 15 years, however, spinal cord injury research has become a focus of neuroscience research. Important new knowledge has been gained, and there is a strong push towards clinical application. The next few years will tell us whether we will be able “to make the lame walk”, to stand-up and move around for short distances from the bed to the kitchen or bathroom, to control their bladder and to breathe autonomously.

Human spinal cord injuries are usually contusions or partial, rarely complete, transections. The primary mechanical damage is followed by a complex process of secondary damage, in which ischaemic and inflammatory processes have a major role. Inflammation seems to have both damaging and tissue-protective effects. Massive axotomies of descending and ascending tracts, local loss of neuronal elements and glial cells, myelin damage and the formation of cysts and scars characterize the pathophysiological evolution of spinal cord injuries 1., 2., 3..

Many injured CNS fibre tracts react to the lesion with a clear, but only short-lasting repair response: they produce sprouts from the cut ends or as collaterals, and the respective cell bodies upregulate growth proteins, such as GAP-43. Sprouting turns into long-distance regeneration in a peripheral nerve environment (e.g. in a nerve graft [4]), but not in CNS tissue, which seems actively to inhibit neurite growth [5].

Three lines of evidence support the crucial role of myelin-associated neurite growth inhibitors in preventing CNS regeneration. First, deleting oligodendrocytes or myelin enhances the regeneration of descending tracts in the differentiated cord of rats, mice and chicken (reviewed in [1]). Second, antibodies against Nogo-A (also called NI-220/250 or IN-1 antigen) applied via the cerebrospinal fluid (from antibody-producing hybridoma implants or pumps) enhance regenerative sprouting and long-distance elongation 6., 7.. Third, autoimmunization of mice or rats with myelin or spinal cord homogenates allows regenerative sprouting and growth after spinal cord lesions [8].

Nogo A was first purified as a high molecular weight, highly inhibitory novel membrane protein of spinal cord myelin 9., 10., and its cDNA was cloned in 2000 11., 12., 13.. The myelin proteins myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) and the proteoglycans V2 and brevican are additional neurite growth inhibitory components found in CNS white matter 14., 15., 16.; however, their roles in regeneration and repair in vivo are still largely unknown. In the present review I summarize the current evidence for the role of Nogo-A in axonal regeneration mechanisms of functional recovery after CNS injury.

Section snippets

The neurite growth inhibitory protein Nogo-A

Nogo-A is a membrane protein of 1163 amino acids (rat sequence, apparent molecular weight 200 kDa) that is expressed in the adult mammalian CNS mainly by oligodendrocytes 11., 12., 13., 17.•, 18.•. The neuronal expression of Nogo-A is pronounced during development but low in the adult nervous system 17.•, 18.•, 19.. The splice form Nogo-B (360 aa, 55 kDa) is found in many tissues and cell types including adult neurons, whereas Nogo-C (190 amino acids, 25 kDa) is expressed mainly in muscle [17].

Neurite growth inhibition by Nogo-A: receptors and intracellular messengers

So far, only one binding site/receptor subunit for Nogo-A has been characterized: the 443-residue glycosyl-phosphatidylinositol-linked, leucine-rich repeat glycoprotein NgR 24., 25., 26.. This receptor binds to the region of 66 amino acids in the C-terminal domain that is common to Nogo-A, -B and -C. Interestingly, NgR also binds to the neurite growth inhibitory myelin proteins MAG and OMgp 15., 27.. It is complexed with the low-affinity p75 nerve growth factor (NGF) receptor, which may act as

Nogo inactivation: in vitro results

The strong inhibitory activity of CNS myelin or CNS tissue extracts in vitro can be partially neutralized by antibodies against Nogo-A, Nogo gene deletions, soluble NgR fragments, NgR blocking peptides, inhibition of Rho-A or ROCK, inhibition of the intracellular calcium rise, or high concentrations of cAMP (Figure 1).

Neutralizing Nogo-A antibodies have been found to significantly decrease the inhibitory activity of CNS myelin 7., 9., 11., 32.. These findings formed the basis of early crucial

Nogo inactivation in vivo in the lesioned spinal cord: anatomical results

The adult rat (or mouse) corticospinal tract (CST) has been the system of choice for many recent studies: the CST is the largest descending tract, which carries myelinated and unmyelinated sensory system and motor fibres. Descending rubrospinal, vestibulospinal and reticulospinal tracts and the monoaminergic systems are, however, of greater importance than the CST for most locomotor and basic vital functions. Their responses to regeneration enhancing treatments, as well as the responses of

Movement control: functional consequences of Nogo inactivation

The current results of experiments in which Nogo has been suppressed in rats or mice with spinal cord injuries are best understood against a background of the physiological concepts underlying movement control. Movements are controlled on different levels in the mammalian CNS: local spinal circuits can generate simple components of movement and rhythmic movements. These circuits are controlled and modified by sensory input (reflexes) and by descending central pathways. Brainstem serotonergic

Enhancing compensatory mechanisms in the injured CNS

Even large spinal cord lesions that are partial can be followed by a considerable degree of functional recovery in humans and rats [56]. Motor recovery takes a few weeks in the rat and several months in humans, and probably depends on compensatory sprouting of spared fibres. So far, only very few studies document these changes on the anatomical level. Thoracic spinal cord lesions including the CST result in spontaneous sprouting of hindlimb CST axons into the cervical spinal cord: forelimb,

Conclusions

The similarity of the results obtained after antibody-mediated neutralization of Nogo-A, Nogo gene deletions, NgR blockade and blockade of the downstream messengers Rho-A and ROCK in rat and mouse models of spinal cord lesion are striking. Enhanced regenerative sprouting and long-distance regeneration (mostly of the CST), as well as an impressive enhancement of functional recovery have been observed. Nogo-A thus seems to be a crucial factor for restricting spontaneous fibre regeneration and

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

I thank D Dodd, L Dimou and L Schnell for critical comments on the manuscript. Work in my laboratory is supported by grants from the Swiss National Science Foundation (31-63633.00), the Swiss National Science Foundation National Centre for Competence in Research (NCCR) ‘Neural Plasticity and Repair’ programme and the Christopher Reeve Paralysis Foundation (Springfield, NJ).

References (62)

  • C.M. Papadopoulos et al.

    Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat

    Ann. Neurol.

    (2002)
  • C. Pot et al.

    Nogo-A expressed in Schwann cells impairs axonal regeneration after peripheral nerve injury

    J. Cell. Biol.

    (2002)
  • N. Weidner et al.

    Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury

    Proc. Natl. Acad. Sci. U S A

    (2001)
  • M. Thallmair et al.

    Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions

    Nat. Neurosci.

    (1998)
  • M.E. Schwab et al.

    Degeneration and regeneration of axons in the lesioned spinal cord

    Physiol. Rev.

    (1996)
  • M.E. Schwab

    Repairing the injured spinal cord

    Science

    (2002)
  • L.H.S. Sekhon et al.

    Epidemiology, demographics, and pathophysiology of acute spinal cord injury

    Spine

    (2003)
  • S. David et al.

    Axonal elongation into peripheral nervous system ‘bridges’ after central nervous system injury in adult rats

    Science

    (1981)
  • M.E. Schwab et al.

    Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors

    J. Neurosci.

    (1985)
  • L. Schnell et al.

    Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors

    Nature

    (1990)
  • C. Brösamle et al.

    Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment

    J. Neurosci.

    (2000)
  • M.S. Chen et al.

    Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1

    Nature

    (2000)
  • T. Grandpré et al.

    Identification of the Nogo inhibitor of axon regeneration as a reticulon protein

    Nature

    (2000)
  • R. Prinhja et al.

    Inhibitor of neurite outgrowth in humans

    Nature

    (2000)
  • B. Niederöst et al.

    Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycan

    J. Neurosci.

    (1999)
  • M.T. Filbin

    Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

    Nat. Rev. Neurosci.

    (2003)
  • S. David et al.

    Molecular approaches to spinal cord repair

    Annu. Rev. Neurosci.

    (2003)
  • A.B. Huber et al.

    Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions

    J. Neurosci.

    (2002)
  • X. Wang et al.

    Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact

    J. Neurosci.

    (2002)
  • A. Josephson et al.

    Nogo mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury

    Exp. Neurol.

    (2001)
  • T. Oertle et al.

    Nogo and its paRTNers

    Trends Cell. Biol.

    (2003)
  • Cited by (537)

    • Neuroplasticity of spinal cord injury and repair

      2022, Handbook of Clinical Neurology
    • Mechanisms and repair strategies for white matter degeneration in CNS injury and diseases

      2021, Biochimica et Biophysica Acta - Molecular Basis of Disease
    View all citing articles on Scopus
    View full text