Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

Belin, Sophie; Ornaghi, Francesca; Shackleford, Ghjuvan’Ghjacumu; Wang, Jie; Scapin, Cristina; Lopez‐Anido, Camila; Silvestri, Nicholas J.; Robertson, Neil; Williamson, Courtney L.; Ishii, Akihiro; Taveggia, Carla; Svaren, John; Bansal, Rashmi; Schwab, Markus H.; Nave, Klaus Armin; Fratta, Pietro; D’Antonio, Maurizio; Poitelon, Yannick; Feltri, M. Laura; Wrabetz, Lawrence

doi:10.1093/hmg/ddy420

Cited by 33 publications

(48 citation statements)

References 96 publications

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“…PMP2 has have high binding affinity to fatty acids and cholesterol [137,138] and is proposed to participate in fatty acid transport and fatty acid metabolism [133,139,140]. Interestingly, several PMP2 mutations were shown to cause a demyelinating form of Charcot-Marie-Tooth disease [141][142][143]; and upregulation of axonal neuregulin signaling causes an increase in PMP2 expression [144,145].…”

Section: Fatty Acid Uptakementioning

confidence: 99%

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

Poitelon

Kopec

Belin

2020

Cells

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211

152

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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.

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Section: Fatty Acid Uptakementioning

confidence: 99%

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

Poitelon

Kopec

Belin

2020

Cells

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211

152

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“…Interestingly, administration of exogenous NRG1 type III and NRG1 type I promotes neurite outgrowth and nerve regeneration (Mahanthappa et al, 1996; Cai et al, 2004). Moreover, modulation of NRG1 activity in animal models of CMT1A (Fledrich et al, 2014), CMT1B (Scapin et al, 2018) and Congenital Hypomyelinating Neuropathy (Belin et al, 2018), can ameliorate the peripheral hypomyelination observed in these diseases, prevent axonal loss and promote nerve functional recovery, the latter all features observed also after nerve injury. Nonetheless, it has also been recently reported that NRG1 is already highly expressed in nerves of CMT1A pre-clinical models, thus indicating that delivery of exogenous NRG1 should be carefully evaluated (Fornasari et al, 2018).…”

Section: Neuregulin-1mentioning

confidence: 99%

The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Pellegatta

Taveggia

2019

Front. Cell. Neurosci.

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After damage, axons in the peripheral nervous system (PNS) regenerate and regrow following a process termed Wallerian degeneration, but the regenerative process is often incomplete and usually the system does not reach full recovery. Key steps to the creation of a permissive environment for axonal regrowth are the trans-differentiation of Schwann cells and the remodeling of the extracellular matrix (ECM). In this review article, we will discuss how proteases and secretases promote effective regeneration and remyelination. We will detail how they control neuregulin-1 (NRG-1) activity at the post-translational level, as the concerted action of alpha, beta and gamma secretases cooperates to balance activating and inhibitory signals necessary for physiological myelination and remyelination. In addition, we will discuss the role of other proteases in nerve repair, among which A Disintegrin And Metalloproteinases (ADAMs) and gamma-secretases substrates. Moreover, we will present how matrix metalloproteinases (MMPs) and proteases of the blood coagulation cascade participate in forming newly synthetized myelin and in regulating axonal regeneration. Overall, we will highlight how a deeper comprehension of secretases and proteases mechanism of action in Wallerian degeneration might be useful to develop new therapies with the potential of readily and efficiently improve the regenerative process.

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“…P2 is a Schwann cell-specific protein expressed in the PNS myelin of tetrapods (10). Intriguingly, P2 is expressed in a mosaic fashion, not being present in all myelin sheaths (11,12). This small βbarrel protein belongs to the family of fatty acid binding proteins (FABPs).…”

mentioning

confidence: 99%

Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

Ruskamo

Krokengen

Kowal

et al. 2020

Journal of Biological Chemistry

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Myelin protein P2 is a peripheral membrane protein of the fatty acid–binding protein family that functions in the formation and maintenance of the peripheral nerve myelin sheath. Several P2 gene mutations cause human Charcot-Marie-Tooth neuropathy, but the mature myelin sheath assembly mechanism is unclear. Here, cryo-EM of myelin-like proteolipid multilayers revealed an ordered three-dimensional (3D) lattice of P2 molecules between stacked lipid bilayers, visualizing supramolecular assembly at the myelin major dense line. The data disclosed that a single P2 layer is inserted between two bilayers in a tight intermembrane space of ∼3 nm, implying direct interactions between P2 and two membrane surfaces. X-ray diffraction from P2-stacked bicelle multilayers revealed lateral protein organization, and surface mutagenesis of P2 coupled with structure-function experiments revealed a role for both the portal region of P2 and its opposite face in membrane interactions. Atomistic molecular dynamics simulations of P2 on model membrane surfaces suggested that Arg-88 is critical for P2-membrane interactions, in addition to the helical lid domain. Negatively charged lipid headgroups stably anchored P2 on the myelin-like bilayer surface. Membrane binding may be accompanied by opening of the P2 β-barrel structure and ligand exchange with the apposing bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step toward deciphering the 3D assembly of a mature myelin sheath at the molecular level.

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Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy

Cited by 33 publications

References 96 publications

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

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

The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice

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