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The Intrinsically Disordered Proteins of Myelin in Health and Disease

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The Intrinsically Disordered Proteins of Myelin in Health and Disease cells Review Flexible Players within the Sheaths: The Intrinsically Disordered Proteins of Myelin in Health and Disease Arne Raasakka 1 and Petri Kursula 1,2,* 1 Department of Biomedicine, University of Bergen, Jonas Lies vei 91, NO-5009 Bergen, Norway; [email protected] 2 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Aapistie 7A, FI-90220 Oulu, Finland * Correspondence: [email protected] Received: 30 January 2020; Accepted: 16 February 2020; Published: 18 February 2020 Abstract: Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbor pathophysiological roles in myelin disease. Many myelin proteins have common attributes, including small size, hydrophobic segments, multifunctionality, longevity, and regions of intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin, and we correlate these with their various functions, including susceptibility to post-translational modifications, function in protein–protein and protein–membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved. Keywords: myelin; intrinsically disordered protein; multiple sclerosis; peripheral neuropathies; myelination; protein folding; protein–membrane interaction; protein–protein interaction 1. Introduction The vertebrate nervous system has evolved to serve a vast diversity of animals, including humans. The brain and the spinal cord form the central nervous system (CNS), which orchestrates information storage and processing, as well as reads sensory output. On the other hand, the peripheral nervous system (PNS) acts as a vital link between the CNS and peripheral organs. While the nervous system is well-organized in terms of nerve tracts, neurons lack sufficient action potential propagation efficiency due to their relatively small diameter (usually 0.1–20 µm) compared to their length (up to ~1 m) [1–3]. Another limitation is the availability of metabolic energy, as sustained nerve impulse firing is an active process that requires ATP—much of which is obtained through mitochondrial activity [4]. The giant squid has solved the efficiency problem through the evolution of giant axons—some up to 1 mm in diameter [5]—but in vertebrates, another solution allows the acceleration of nerve impulses up to 100-fold: axon insulation by myelin. Myelin is a specialized plasma membrane produced by myelinating glia: oligodendrocytes in the CNS and Schwann cells in the PNS. The myelin membrane is wrapped around axons tens of times and compacted in a process driven by actin disassembly and membrane stacking via abundant adhesion proteins [6,7]. The outcome is a lipid-rich sheath with low water content, separating the Cells 2020, 9, 470; doi:10.3390/cells9020470 www.mdpi.com/journal/cells Cells 2020, 9, 470 2 of 33 Cells 2020, 9, 470 2 of 34 axonalaxonal surface surface from from the the extracellular extracellular milieu. milieu. In In th thee CNS, CNS, oligodendrocytes oligodendrocytes grow grow long long processes processes that that formform single single myelin myelin units; units; however, however, a single a single oligodendrocyte oligodendrocyte can myelinate can myelinate several several axons. axons. In the InPNS, the eachPNS, Schwann each Schwann cell wraps cell around wraps aroundan axon an and axon forms and one forms myelin one myelinunit (Figure unit (Figure1). Individual1). Individual myelin unitsmyelin along units the along axon theare axonseparated are separated by nodes byof Ranvier, nodes of where Ranvier, the where axonal the membrane axonal membrane is rich in voltage- is rich in gatedvoltage-gated ion channels. ion channels. Electrical Electrical insulation insulation and the andarrangement the arrangement of ion channel of ion channel clusters clusters form the form basis the ofbasis saltatory of saltatory conduction conduction [8]. [8]. FigureFigure 1. 1. TheThe anatomy anatomy of of oligodendrocytic oligodendrocytic and and Schwann Schwann cell cell myelin myelin sheaths sheaths in in the the central central nervous nervous systemsystem (CNS) (CNS) and peripheralperipheral nervous nervous system system (PNS), (PNS), respectively. respectively. The The arrangement arrangement of multiple of multiple myelin myelinunits alongunits analong axon an is axon illustrated, is illustrated, as well as unwrappedwell as unwrapped myelin unitsmyelin and units cross and sections. cross sections. Compact Compactmyelin and myelin non-compact and non-compact myelin are myelin colored are bluecolored and blue gray, and respectively. gray, respectively. Abbreviations: Abbreviations: Ab, abaxonal Ab, abaxonallayer; Ad, layer; adaxonal Ad, adaxonal layer; BL, layer; basal lamina;BL, basal IM, lami innerna; mesaxon;IM, inner IPL,mesaxon; intraperiod IPL, intraperiod line; LIs, longitudinal line; LIs, longitudinalincisures; MDL, incisures; major MDL, dense line;major OM, dense outer line; mesaxon; OM, outer PAS, mesaxon; periaxonal PAS, space; pe PNC,riaxonal paranodal space; PNC, collar; paranodalRCs, radial collar; components; RCs, radial SLI, componen Schmidt–Lantermants; SLI, Schmidt–La incisures.nterman incisures. TheThe overall overall morphology morphology of of myelin myelin is is similar similar in in the the CNS CNS and and PNS, PNS, but but there there are are notable notable ultrastructuralultrastructural differences. differences. Most Most of of the the myelin myelin sheath sheath is is compact compact myelin—tightly myelin—tightly stacked stacked proteolipid proteolipid membranemembrane multilayers multilayers with with low low water water content. content. This This promotes promotes the the insulative insulative character character of of myelin. myelin. Non-compactNon-compact myelin myelin lines lines the the outer- outer- and and innermost innermost layers layers of of myelin, myelin, known known as as the the abaxonal abaxonal and and adaxonaladaxonal layers, layers, respectively. respectively. Additionally, Additionally, it it forms forms paranodal paranodal loops—structures loops—structures at at the the ends ends of of the the myelinmyelin unit unit that that anchor anchor it it to the axon. CytoplasmicCytoplasmic channelschannels thatthat traversetraverse through through compact compact myelin myelin in inthe the PNS PNS and and CNS CNS are known are known as Schmidt–Lanterman as Schmidt–Lant incisureserman incisures and longitudinal and longitudinal incisures, respectively.incisures, respectively.Water is abundant Water is in abundant non-compact in non-compact myelin, which myelin, contains which cytoskeletal contains cytoskeletal elements and elements serves and as a servesmaintenance as a maintenance compartment compartment in the myelin in the sheath myelin (Figure sheath1)[ (Figure4,9]. 1) [4,9]. InIn the the PNS,PNS, thethe myelin myelin sheath sheath is surrounded is surrounded by a carbohydrate-richby a carbohydrate-rich basal lamina; basal suchlamina; a structure such a is structurenot present is innot CNS present myelin in [CNS10]. Additionally, myelin [10]. the Additionally, abaxonal space the ofabaxonal Schwann space cells isof partially Schwann compacted cells is partiallyto so-called compacted membrane to so-called appositions, membrane which line appositions, veins of cytoplasm which line known veins as of Cajal cytoplasm bands. known Membrane as Cajalappositions bands. andMembrane Cajal bands appositions are required and for Cajal the correct bandsfunction are required of PNS for myelin, the correct but the function role of membrane of PNS myelin,appositions but the is poorlyrole of understoodmembrane appositions [11–13]. The is space poorly that understood separates [11–13]. the adaxonal The space membrane that separates from the theaxonal adaxonal membrane membrane is the periaxonal from the space,axonal in membrane which axoglial is the signaling periaxonal and adhesionspace, in take which place axoglial [14]. signalingThe and narrow adhesion extracellular take place space [14]. between the periodic compact myelin membranes is called the intramyelinicThe narrow compartment. extracellular The space lipid-rich between myelin the membrane periodic compact carries a highmyelin content membranes of cholesterol, is called which the is intramyelinicessential for myelinationcompartment. [15 ,The16]. Thelipid-rich myelin myelin membrane membrane is asymmetric: carries athe high extracellular content of/ intramyeliniccholesterol, whichmonolayer is isessential rich in glycolipids, for myelination whereas the[15,16]. cytoplasmic The leafletmyelin is predominantly membrane formedis asymmetric: of phospholipids the extracellular/intramyelinic monolayer is rich in glycolipids, whereas the cytoplasmic leaflet is predominantly formed of phospholipids and harbors a net negative charge [17]. This charge
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