Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination.

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria

GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADGRG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin

Influence of Mechanical Stimuli on Schwann Cell Biology

Schwann cells are the glial cells of the peripheral nervous system (PNS). They insulate axons by forming a specialized extension of plasma membrane called the myelin sheath. The formation of myelin is essential for the rapid saltatory propagation of action potentials and to maintain the integrity of axons. Although both axonal and extracellular matrix (ECM) signals are necessary for myelination to occur, the cellular and molecular mechanisms regulating myelination continue to be elucidated. Schwann cells in peripheral nerves are physiologically exposed to mechanical stresses (i.e., tensile, compressive and shear strains), occurring during development, adulthood and injuries. In addition, there is a growing body of evidences that Schwann cells are sensitive to the stiffness of their environment. In this review, we detail the mechanical constraints of Schwann cells and peripheral nerves. We explore the regulation of Schwann cell signaling pathways in response to mechanical stimulation. Finally, we provide a comprehensive overview of the experimental studies addressing the mechanobiology of Schwann cells. Understanding which mechanical properties can interfere with the cellular and molecular biology of Schwann cell during development, myelination and following injuries opens new insights in the regulation of PNS development and treatment approaches in peripheral neuropathies

Lamines A et syndromes progéroïdes. Une farnésylation persistante aux conséquences dramatiques

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Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

Myelin is critical for the proper function of the nervous system and one of the most complex cell–cell interactions of the body. Myelination allows for the rapid conduction of action potentials along axonal fibers and provides physical and trophic support to neurons. Myelin contains a high content of lipids, and the formation of the myelin sheath requires high levels of fatty acid and lipid synthesis, together with uptake of extracellular fatty acids. Recent studies have further advanced our understanding of the metabolism and functions of myelin fatty acids and lipids. In this review, we present an overview of the basic biology of myelin lipids and recent insights on the regulation of fatty acid metabolism and functions in myelinating cells. In addition, this review may serve to provide a foundation for future research characterizing the role of fatty acids and lipids in myelin biology and metabolic disorders affecting the central and peripheral nervous system

Two novel missense mutations in FGD4/FRABIN cause Charcot-Marie-Tooth type 4H (CMT4H)

International audienceBy sequencing of the FGD4 coding sequence in a cohort of 101 patients affected by autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT), we have identified two novel missense mutations in FGD4 in two patients from consanguineous descent: p.Arg442His in an Algerian patient and p.Met566Ile in a Lebanese girl. The patients present early onset, slowly progressive CMT, with drastic reduction of nerve conduction velocities. These mutations are the second and third missense mutations characterized in FGD4. They are likely to lead to conformational changes in the PH1 and FYVE domains