Claire Jacob

The stratum corneum represents the main barrier to transdermal drug delivery, particularly for hydrophilic and ionized compounds such as aminophylline. In

After a peripheral nerve injury, Schwann cells (SCs), the myelinating glia of the peripheral nervous system, convert into repair cells that foster axonal regrowth, and then remyelinate or re-ensheath regenerated axons, thereby ensuring functional recovery. The efficiency of this mechanism depends however on the time needed for axons to regrow. Here, we show that ablation of histone deacetylase 8 (HDAC8) in SCs accelerates the regrowth of sensory axons and sensory function recovery. We found that HDAC8 is specifically expressed in sensory SCs and regulates the E3 ubiquitin ligase TRAF7, which destabilizes hypoxia-inducible factor 1-alpha (HIF1α) and counteracts the phosphorylation and upregulation of c-Jun, a major inducer of the repair SC phenotype. Our study indicates that this phenotype switch is regulated by different mechanisms in sensory and motor SCs and is accelerated by HDAC8 downregulation, which promotes sensory axon regeneration and sensory function recovery.

Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), react to a PNS injury by converting into repair cells that foster axonal regrowth, and then remyelinate or re-ensheath regenerated axons, thereby ensuring functional recovery. The efficiency of this mechanism depends however on the time needed for axons to regrow. Here, we show that ablation of histone deacetylase 8 (HDAC8) in SCs accelerates the regrowth of sensory axons and sensory function recovery. We found that HDAC8 is specifically expressed in sensory SCs and regulates the E3 ubiquitin ligase TRAF7, which destabilizes hypoxia-inducible factor 1-alpha (HIF1a) and counteracts the phosphorylation and upregulation of c-Jun, a major inducer of the repair SC phenotype. Our study demonstrates that this phenotype switch is regulated by different mechanisms in sensory and motor SCs and is accelerated by HDAC8 downregulation, which promotes sensory axon regeneration and sensory function recovery.

After a spinal cord injury, axons fail to regrow, which results in permanent loss of function ¹ . This is in contrast with peripheral axons that can regrow efficiently after injury ² . These differences are partly due to the different plasticity of myelinating cells, Schwann cells and oligodendrocytes, in these two systems ³ . The molecular mechanisms underlying this different plasticity remain however poorly understood. Here, we show that the phosphatase Dusp6 ⁴ is a master inhibitor of oligodendrocyte plasticity after spinal cord injury. Dusp6 is rapidly downregulated in Schwann cells and upregulated in oligodendrocytes after axon injury. Simultaneously, the MAP kinases ERK1/2 are activated and the transcription factor c-Jun is upregulated in Schwann cells ^5,6 , but not in oligodendrocytes. Ablation or inactivation of Dusp6 induces rapid ERK1/2 phosphorylation, c-Jun upregulation and filopodia formation in oligodendrocytes, leading to mechanically-induced, fast disintegration of distal ends of injured axons, myelin clearance and axonal regrowth. Together, our findings provide understanding of the mechanisms underlying the different plasticity of Schwann cells and oligodendrocytes after injury and a method to convert mature oligodendrocytes exhibiting inhibitory cues for axonal regrowth into repair oligodendrocytes reminiscent of repair Schwann cells. We show that repair oligodendrocytes successfully increase the compatibility of the spinal cord environment with axonal regrowth after injury, suggesting a potential use of repair oligodendrocytes as future therapeutic approach to treat spinal cord injuries.

All currently licensed medications for multiple sclerosis (MS) target the immune system. Albeit promising preclinical results demonstrated disease amelioration and remyelination enhancement via modulating oligodendrocyte lineage cells, most drug candidates showed only modest or no effects in human clinical trials. This might be due to the fact that remyelination is a sophistically orchestrated process that calls for the interplay between oligodendrocyte lineage cells, neurons, central nervous system (CNS) resident innate immune cells, and peripheral immune infiltrates and that this process may somewhat differ in humans and rodent models used in research. To ensure successful remyelination, the recruitment and activation/repression of each cell type should be regulated in a highly organized spatio–temporal manner. As a result, drug candidates targeting one single pathway or a single cell population have difficulty restoring the optimal microenvironment at lesion sites for remyelination. Therefore, when exploring new drug candidates for MS, it is instrumental to consider not only the effects on all CNS cell populations but also the optimal time of administration during disease progression. In this review, we describe the dysregulated mechanisms in each relevant cell type and the disruption of their coordination as causes of remyelination failure, providing an overview of the complex cell interplay in CNS lesion sites.

Schwann cells, the myelinating glia of the peripheral nervous system, wrap axons multiple times to build their myelin sheath. Myelin is of paramount importance for axonal integrity and fast axon potential propagation. However, myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal, demyelinating or dysmyelinating, or as intermediate. The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes: peripheral myelin protein 22, myelin protein zero and gap junction beta 1 (coding for Connexin 32) causing Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1B, and X-linked Charcot-Marie-Tooth disease type 1, respectively. The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients. No treatment to cure or slow down the disease progression is currently available on the market, however, scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies. In this review, we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease, the rodent models used in research, and the emerging therapeutic approaches to cure or counteract the progression of the disease.

Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.

The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.