AlphaB-crystallin regulates remyelination after peripheral nerve injury

Abstract

AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.T he robust regenerative capacity of the damaged peripheral nervous system (PNS) is partly determined by cellular and molecular events that occur in the nerve segment distal to the injury site (1). For instance, during Wallerian degeneration, influx of calcium into the damaged nerve within 12-24 h of PNS injury activates proteases (2) that result in cytoskeletal breakdown and subsequent disintegration of the axon membrane. This axon degeneration is then followed by breakdown of the myelin sheath within 2 d (3). Schwann cells, the glial cells that characterize the PNS, subsequently undergo a number of reactive physiological changes that benefit the damaged axon. Within 48 h of peripheral nerve damage, myelinating Schwann cells decrease their expression of myelin proteins, such as myelin basic protein (MBP), peripheral myelin protein 22, and protein 0 (P0) (4), and along with their nonmyelinating counterparts, revert to a nonmyelinating phenotype (4). At ∼3-4 d postinjury, the dedifferentiated Schwann cells proliferate (5-7) and align within the basal lamina to form bands of Büngner that provide a structural and trophic supportive substrate for regenerating axons. These Schwann cells secrete neurotrophic factors that provide trophic sustenance to damaged neurons until they reestablish contact with their targets (8) and produce extracellular matrix molecules that encourage and guide outgrowing axons (9), whereas secretion of chemokines is thought to mediate the infiltration of blood-derived macrophages, which along with Schwann cells, phagocytose myelin debris and its associated axon growth inhibitors (9). Finally, based on the level of neuregulin 1 Types I and III on Schwann cells and axons, respectively, and their binding to their cognate receptors ErbB2/ ErbB3 on Schwann cells, these glia will revert to a myelinating or ensheathing phenotype on contact with regrowing axons (10). Altogether, these morphological and physiological changes in Schwann cells create an environment that encourages longdistance axon growth.In humans, however, regrowth of damaged peripheral nerves is often incomplete, wh...

Heat shock protein that facilitates myelination of regenerating axons

“…Although αBC was first thought to be found only as a structural protein in the lens, it was later identified as a small (∼22 kDa) heat shock protein (also known as HspB5 and CRYAB) and was present in other tissues in addition to the lens, including the sciatic nerve (14,15). In culture, αBC is expressed in both myelinating and nonmyelinating Schwann cells from the rat, and it is present both during development and (12) to speculate that the protein was involved in myelination in the PNS. αBC was also reported to be present in the CNS in multiple sclerosis lesions and in the corresponding animal model of multiple sclerosis, experimental autoimmune encephalomyelitis.…”

“…Experiments on experimental autoimmune encephalomyelitis revealed more severe inflammation and demyelination in the CNS in mice in which αBC had been knocked out than in WT animals (17). Lim et al (12) examined the role of αBC on the PNS in adult mice after crushing the sciatic nerve unilaterally. In vivo in the mouse, αBC was found to colocalize with both myelinating Schwann cells and axons, but not nonmyelinating Schwann cells.…”

“…As (12) examined the ratio of myelinating and nonmyelinating Schwann cells in animals after axotomy. They found that the total number of Schwann cells did not differ between genotypes nor did the ratio of myelinating to nonmyelinating cells at early times after axotomy.…”

“…Neuregulin 1 type III is a key signal between intact axons and Schwann cells and has a number of effects, including the promotion of myelination (18,19). Lim et al (12) report that axonal neuregulin decreases dramatically in the distal nerve segment after a sciatic nerve crush in WT mice and then rebounds, whereas the decrease in αBC −/− mice is much smaller. However, the relationship between this difference and the hypomyelination seen in the mutant is not examined.…”

“…Some other questions not addressed in the Lim et al (12) paper concern the relative importance of axonal and Schwann cell αBC in regulating myelination, the extent to which αBC acts intracellularly or extracellularly, and the receptors on which exogenous and endogenous αBC act. One might expect that axonal αBC is cleared fairly rapidly during Wallerian degeneration and, therefore, might not account for the delayed effects attributed to αBC after injury.…”