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Cellular and Molecular Responses in the Peripheral and Central Nervous System Following Axonal Injury


This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

  • Peripheral nerve injury may be characterized via a three-tier system that includes neurapraxic, axonotmetic, and neurotmetic injuries.

  • Neurotrophins aid in Schwann cell migration and macrophage response to axonal regeneration in the PNS.

  • CNS oligodendrocytes produce growth-inhibitory molecules, yet this response is delayed compared with that of macrophages in the PNS.

  • Chondroitin sulfate proteoglycans in the CNS help form perineuronal nets that guide plasticity after neuronal deafferentiation.

  • Analysis of cellular and molecular responses in the CNS and PNS may lead to improved therapeutics for injuries.

Cellular and Molecular Responses in the Peripheral and Central Nervous Systems

From at least the time of Santiago Ramon y Cajal, the promise of nerve regeneration has captivated and frustrated scientists and clinicians alike. Since the Nobel Laureate’s early studies in the late 19th century, we have learned much about the cellular and molecular mechanisms underlying PNS and CNS injury and recovery. Long-distance axonal regeneration can occur in the PNS to a much greater extent than in the adult mammalian CNS, where little if any occurs. The local environment is fundamentally important to this differing capacity for regeneration. Whereas motor neuron cell bodies reside in the CNS, their axons respond differently in the spinal cord compared with the peripheral nerve. But even in the PNS, regeneration after injury is not a forgone conclusion. Cell bodies must survive. Proximal injuries, complex nerve branching patterns, distant targets, and increased time since injury all reduce regeneration. Atrophy of target structures such as muscle reduces reinnervation.

Although several other chapters deal with related topics, this chapter focuses on the cellular and molecular mechanisms underlying neural injury in both the PNS and CNS. A thorough understanding of injury mechanisms allows for rational approaches to therapeutic intervention. Several examples of rational interventions to promote axonal regeneration by increasing beneficial factors and reducing negative cellular and molecular factors are discussed.

Peripheral Nervous System Response to Injury

In 1942, Seddon described a three-tier system for categorizing peripheral nerve injury that is still widely used today. Neurapraxic injuries are the mildest form, in which myelin injury causes a temporary deficit, but recovery is faster than could be possible with regeneration. Axonotmesis is a medium-grade injury in which axonal continuity is disrupted but the supporting structures remain intact. Wallerian degeneration occurs distal to the point of direct axonal injury, but intact Büngner bands, composed of remaining extracellular matrix–lined microchannels, maintain an environment conducive to axonal growth and regeneration. In contrast, neurotmesis is the most severe grade of nerve injury, in which not only is there an interruption in axonal continuity, but the surrounding structures that support axonal growth are either absent in the case of a gap or overwhelmed by cellular factors (i.e., fibroblastic proliferation producing extensive intraneural fibrosis) and molecular factors that impede axonal regeneration. In such cases, axonal regeneration does not occur without surgical intervention and repair, with or without a graft depending on the length of the damaged segment of nerve. In the PNS, recovery from neurapraxic and axonotmetic injuries is possible as a result of a constellation of cellular and molecular factors that create a more permissive environment for remyelination and axonal regeneration relative to the CNS.

The establishment of laboratory models for nerve stretch injury, a common mechanism in clinical traumatic injuries especially involving the brachial plexus, has deepened our understanding of nerve injury pathophysiology. Biomechanical experiments utilizing rodent sciatic nerves subjected to a weight drop test suggest that nerve injuries fall into distinct biomechanical patterns: elastic, inelastic, and rupture injuries. Elastic stretch injury refers to segments of nerve that return to pre-injury length, whereas inelastic injuries occur in zones of the nerve that have undergone significant internal structural damage leading to permanent elongation of the nerve. Nerve rupture occurs in a threshold-specific matter in response to sufficient stretch force. On a histological scale, nerve stretch injury results in graded disruption of the nerve microarchitecture with loss of fiber undulation and rupture of individual nerve fibers. Such experiments may provide further nerve injury models that are necessary to guide surgical intervention.

Cell Body Survival

Neurotrophic factors are prevalent in the distal peripheral nerve stump after axonal injury occurs. Namely, nerve growth factor (NGF) and other neurotrophic factors such as neurotrophin-3 (NT-3) aid in the survival of sympathetic and sensory neurons. They are transported to neuronal cell bodies via retrograde axonal transport after binding to tyrosine kinase receptors and the NGF receptor p75. , A decrease in NGF and other neurotrophic factors as a result of injury thus impairs an important signal for cell body survival.

Neurotrophins play a major role in promoting cell survival once an axon is injured, without directly affecting the regeneration of axons (their trophic actions). NGF may increase the migration and response of Schwann cells to axotomy. Neurotrophic factors (their tropic actions) can be used to promote adhesion and migration of regenerating axons. NGF applied to nerve bridges increases the rate by which Schwann cells travel to the site of cell injury, subsequently upregulating angiogenesis and improving the recovery rate. NGF applied to these nerve bridges also slows chromatolysis and the associated signs of axotomy.

Cell-intrinsic Mechanisms of Axonal Degeneration

The discovery of the spontaneous Wallerian degeneration slow (WLDs) gene mutation in mice, which encodes a fusion protein consisting of the full length Nmnat1 and the first 80 amino acids of Ube4b, has provided significant insight into the molecular mechanisms of axon degeneration. Axons expressing the WLDs transgene can survive for weeks following axotomy before undergoing Wallerian degeneration. Endogenous Nmnat1, one of three isoforms of the enzyme that catalyzes NAD+, is confined to the nucleus, and its overexpression does not confer axonal survival, however direct transduction of Nmnat1 into the axonal compartment delays axonal degeneration. The isoform Nmnat2, which also catalyzes the synthesis of NAD+, has a short half-life and is shipped to the axon through anterograde transport, and it is thought to be the key endogenous axon survival factor. Knockdown of Nmnat2 in cultured neurons taken from mice and Drosophila results in axonal degeneration in the absence of axonal injury. Taken together, these findings suggest that the chimeric WLDs mutation confers axon protection by localizing Nmnat1 to the axonal compartment, which continues to provide a source of NAD+ after endogenous Nmnat2 levels drop.

Genetic screens in Drosophila have provided insight into genes involved in promoting axon death. SARM1 (sterile alpha and TIR motif-containing 1) encodes a protein that is necessary for axonal degeneration. In the uninjured state, SARM1 is localized to the axon but is inactive, requiring axonal injury to dimerize and enable its active state. Once dimerized, SARM1 facilitates axonal destruction by rapidly depleting NAD+ and ATP levels, which leads to cytoskeletal degradation. Knockout of SARM1 prevents vincristine-mediated peripheral neuropathy in mice. Together, these advances suggest that axon degeneration is an active and regulated process akin to cellular apoptosis. Further research into the molecular underpinnings of axonal degeneration may reveal drug targets that slow or prevent axonal death in traumatic, neurodegenerative, or toxic axonal disorders.

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