Promoting peripheral myelin repair

Zhou, Ye; Notterpek, Lucia

doi:10.1016/j.expneurol.2016.04.007

Cited by 42 publications

(32 citation statements)

References 102 publications

(123 reference statements)

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“…Despite the remarkable axonal regeneration capacity of peripheral nerves, myelin sheaths regenerated after injury are substantially thinner than myelin formed during development 4,5 . Slow and compromised remyelination could contribute to the limited restoration of sensory and motor functions observed after proximal nerve injury in humans 29,46 .…”

Section: Discussionmentioning

confidence: 98%

“…Deficient myelination or failure to properly remyelinate contributes to functional deficits in peripheral nerves after injury and various forms of peripheral neuropathies 1–3 . Myelin sheaths are often the primary site of damage during the initial stages of pathological insults 4 . Despite the regenerative capacity retained in peripheral nerves after injury and disease in humans, remyelination occurs at a slow rate and is ultimately compromised with a thinner myelin sheath, resulting in incapacitating defects in functional reinnervation of the target tissue and sensorimotor function recovery and in neuropathic pain 3,5 .…”

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confidence: 99%

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A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Zhang

Queme

et al. 2018

Nat Med

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Deficits in Schwann cell–mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin–PI3K–AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell–specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3–TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Zhang

Queme

et al. 2018

Nat Med

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“…Schwann cells, however, have two distinct different phenotypes during peripheral nerve regeneration. At an early stage following peripheral nerve injury, Schwann cells go through dedifferentiation and proliferation while, at relatively later time points, Schwann cells go through migration and redifferentiation (Glenn and Talbot, 2013;Ness et al, 2013;Zhou and Notterpek, 2016). Therefore, molecules that exhibit an expression trend whereby their levels change over time might affect both the dedifferentiation and the redifferentiation processes in Schwann cells.…”

Section: Discussionmentioning

confidence: 99%

Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury

Liu

Wang

et al. 2019

Journal of Cell Science

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Tau protein (encoded by the gene microtubule-associated protein tau, Mapt) is essential for the assembly and stability of microtubule and the functional maintenance of the nervous system. Tau is highly abundant in neurons and is detectable in astrocytes and oligodendrocytes. However, whether tau is present in Schwann cells, the unique glial cells in the peripheral nervous system, is unclear. Here, we investigated the presence of tau and its coding mRNA, Mapt, in cultured Schwann cells and find that tau is present in these cells. Gene silencing of Mapt promoted Schwann cell proliferation and inhibited Schwann cell migration and differentiation. In vivo application of Mapt siRNA suppressed the migration of Schwann cells after sciatic nerve injury. Consistent with this, Mapt-knockout mice showed elevated proliferation and reduced migration of Schwann cells. Rats injected with Mapt siRNA and Mapt-knockout mice also exhibited impaired myelin and lipid debris clearance. The expression and distribution of the cytoskeleton proteins α-tubulin and F-actin were also disrupted in these animals. These findings demonstrate the existence and biological effects of tau in Schwann cells, and expand our understanding of the function of tau in the nervous system.

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“…Several trophic factors like neurotrophins, neurogulin 1/ErbB signal, the ADAM secretase family, small molecules like apolipoprotein E, ascorbic acid, etc. play a critical role in the maintenance and repair of the PNS (Taveggia, ; Zhou & Notterpek, ). Conditional knockout of NgR1‐I in Schwann cells results in severe defects in remyelination.…”

Section: Demyelination and Remyelination After Injurymentioning

confidence: 99%

Axonal regeneration in zebrafish spinal cord

Ghosh

Hui

2018

Regeneration

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In the present review we discuss two interrelated events—axonal damage and repair—known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals.

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Promoting peripheral myelin repair

Cited by 42 publications

References 102 publications

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Tau modulates Schwann cell proliferation, migration and differentiation following peripheral nerve injury

Axonal regeneration in zebrafish spinal cord

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