Actin Polymerization Is Essential for Myelin Sheath Fragmentation during Wallerian Degeneration

Abstract

The mechanisms that trigger Wallerian degeneration (WD) of peripheral nerves after injury are not well understood. During the early period of WD, fragmentation of myelin into ovoid structures occurs near the Schmidt-Lantermann incisures (SLI), a noncompact region of the myelin sheath containing autotypical adherens junction. In this study, we found that new filamentous actin polymerization occurs in the SLI of mouse sciatic nerves after injury and that its inhibition prevented not only the degradation of E-cadherin in the SLI but also myelin ovoid formation. However, the inhibition of actin polymerization could not block Schwann cell dedifferentiation. The activation of Rac GTPase was observed in the distal stump of the injured nerves, and a specific Rac inhibitor, a dominant-negative Rac, and Rac1-RNA interference blocked myelin ovoid formation. Together, these findings suggest that dynamic changes in actin in the SLI are essential for initiation of demyelination after peripheral nerve injury.

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

“…Nerve injury is usually followed by wallerian degeneration characterized by axonal degeneration, degradation of the myelin sheath and its fragmentation into small ovoid-like structures [45,46] .…”

Glial Cell Plasticity During Development and Myelinopathies

“…Since actin dynamics are essential mediators of developmental myelination (Nawaz et al, 2015;Zuchero et al, 2015), and are also involved in myelin membrane fragmentation following peripheral nerve injuries (Jung et al, 2011), it is reasonable to hypothesize that the dynamic rearrangement of filamentous actin within the oligodendrocyte cytoskeleton may actively mediate the myelin membrane changes we observed following a demyelinating insult. Future studies are needed to investigate whether actin dynamics are actively changing the oligodendrocyte cytoskeleton to form myelin ovoids in response to a demyelinating insult, or to determine if filamentous actin rearrangement is responding passively to myelin membrane changes.…”

“…Specifically, filamentous actin (F-actin) is integral for initiating myelin wrapping and, upon completion of myelination, F-actin is disassembled from the inner tongue/leading edge and becomes localized to the lateral edges of the myelin sheath (Nawaz et al, 2015;Samanta & Salzer, 2015;Zuchero et al, 2015). Interestingly, actin polymerization is involved in peripheral myelin fragmentation and ovoid / onion bulb formation following injury in vitro, and inhibiting actin polymerization prevents myelin ovoid formation (Jung et al, 2011). Furthermore, cytoskeletal plasticity was recently identified as an important component of demyelination, suggesting that mechanisms within the oligodendrocyte cytoskeleton may be actively involved in reacting to demyelinating insults (Locatelli et al, 2015).…”

“…Actin dynamics are essential for myelin sheath formation and it is reasonable to assume it has an integral role in kinetics underlying de-and re-myelination. Following in vitro peripheral nerve injuries, actin polymerization is involved in the formation of onion bulbs as inhibiting actin polymerization prevents the ovoid or onion bulb from forming (Jung et al, 2011), demonstrating that actin polymerization is actively involved in myelin membrane sheath changes. Furthermore, mechanisms within the oligodendrocyte cytoskeleton may be actively involved in reacting to demyelinating insults as β-actin and β-tubulin gene transcription are upregulated in response to diphtheria-toxin oligodendrocyte death and EAE autoimmune inflammation (Locatelli et al, 2015).…”

“…Additionally, the actin cytoskeleton is involved with the formation of onion bulbs following in vitro peripheral nerve injuries as inhibiting actin polymerization prevented the formation of ovoids, or these onion bulb structures (Jung et al, 2011). Since actin dynamics are essential mediators of developmental myelination (Nawaz et al, 2015;Zuchero et al, 2015), and are also involved in myelin membrane fragmentation following peripheral nerve injuries (Jung et al, 2011), it is reasonable to hypothesize that the dynamic rearrangement of filamentous actin within the oligodendrocyte cytoskeleton may actively mediate the myelin membrane changes we observed following a demyelinating insult.…”