Heat shock protein that facilitates myelination of regenerating axons

Abstract

It is widely recognized that neurons in the peripheral nervous system (PNS) are capable of regeneration after injury. In contrast, those neurons that are entirely located within the CNS (i.e., the brain and spinal cord) largely do not regenerate. What is often not emphasized, however, is that the extent of PNS regeneration is limited and that this results in incomplete functional recovery (1). A great deal of attention has been focused recently on the cellular and molecular mechanisms underlying degeneration and regeneration in the PNS, with an eye toward enhancing this regeneration.Regeneration is not a neuron-autonomous process, but depends heavily on interactions between neurons, glial cells (i.e., Schwann cells in the nerve and satellite cells in peripheral ganglia), and immune cells, particularly macrophages (2, 3). Among the several reasons that have been postulated for the incomplete regeneration in the PNS, is the extremely slow rate of this regeneration (about 1-2 mm per day), leading perhaps to an eventual decrease in the intrinsic growth capacity of the injured axons and the limited period after injury during which Schwann cells actively promote axonal elongation (4).Once an axon is transected or crushed (referred to as axotomy), the distal segment fragments and then is cleared by phagocytic cells by a process called Wallerian degeneration. Advances in our understanding of the mechanism of Wallerian degeneration have come from genetic studies on the mutant gene WLD s and its normal counterpart NMNAT1, both of which temporarily protect the axon from degeneration (5), and SARM1, which is involved in triggering axon degeneration (6, 7). Schwann cells upregulate their expression and release of the macrophage chemokine CCL2, which draws in inflammatory monocytes that then differentiate into macrophages and are involved in phagocytosis of myelin and axonal debris (2). Although it was previously believed that these macrophages played an essential role in Wallerian degeneration, studies with a mouse strain in which the CCL2 receptor CCR2 is knocked out indicate that compensatory phagocytic mechanisms are possible (8).Two types of adult Schwann cells exist: myelinating and nonmyelinating. Nonmyelinating Schwann cells are also the developmental precursor of the myelinating cell. During Wallerian degeneration, the myelinating Schwann cell dedifferentiates and ceases to synthesize myelin proteins (3). This dedifferentiation process is controlled by "a balance between two opposing transcriptional programs": the myelinating program involves transcription factors like Krox20, whereas the nonmyelinating involves factors like cJun (9). Recently, it was shown that these Schwann cell changes can be mimicked by the activation of an inducible Raf kinase transgene (10). What might trigger this induction in situ after injury is not yet known.Axons in the proximal stump of the severed nerve exhibit an initial period of dieback (11) but then form growth cones and begin to elongate. These initial axonal sprouts are not myelina...

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“…These does (59,(62)(63)(64). In the altered pathways in the overexpressed genes, astrocyte development and myelinization were found de/regulated, although we couldn't identify the status of cryab phosphorylation due to the experimental design of our study, the fact that the myelinization pathway is increased and that, as previously described, cryab is involved in favoring this process in the peripheral nervous system, could suggest that the increase of the cryab expression in the pfc exerts a cytoprotective effect (65,66). However, additional studies are needed to define the protein real function in normal aging.…”

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