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Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives

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Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives cells Review Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives Stefano Raffaele , Marta Boccazzi and Marta Fumagalli * Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; [email protected] (S.R.); [email protected] (M.B.) * Correspondence: [email protected]; Tel.: +39-0250318307 Abstract: Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) Citation: Raffaele, S.; Boccazzi, M.; have also been examined to provide insights on future therapeutic interventions. On this basis, we Fumagalli, M. Oligodendrocyte discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating Dysfunction in Amyotrophic Lateral potential or capability to enhance energy metabolism. Sclerosis: Mechanisms and Therapeutic Perspectives. Cells 2021, Keywords: oligodendrocytes; amyotrophic lateral sclerosis (ALS); remyelination; neurodegenerative 10, 565. https://doi.org/10.3390/ disease; regenerative medicine; oligodendrocyte precursor cells (OPCs); GPR17 receptor; glial cells; cells10030565 monocarboxylate transporter 1 (MCT1) Academic Editors: Nadia D’Ambrosi, Savina Apolloni and Mauro Cozzolino 1. Introduction Received: 5 February 2021 Oligodendrocytes (OLs) are highly specialized cells of the central nervous system Accepted: 2 March 2021 (CNS) whose primary function is to form myelin, the lipid-rich structure organized in Published: 5 March 2021 multi-layered sheaths around neuronal axons. Myelin sheath is important to assure long- term axonal integrity by means of metabolic and trophic support and is essential for rapid Publisher’s Note: MDPI stays neutral electrical nerve conduction [1]. with regard to jurisdictional claims in In recent years, the impact of OL loss and myelin dysfunction in a variety of neurode- published maps and institutional affil- generative disorders, including amyotrophic lateral sclerosis (ALS), has become increas- iations. ingly clear. OL injury and demyelination, namely the damage to myelin structure, are now considered major contributors to the disability progression of neurological diseases [2,3]. These harmful events trigger a spontaneous repair process, known as remyelination, during which the oligodendrocyte precursor cells (OPCs), that persist in a quiescent state within Copyright: © 2021 by the authors. the adult CNS [4,5], are activated, migrate, and differentiate to replace the OLs lost during Licensee MDPI, Basel, Switzerland. pathological conditions [6]. However, the efficacy of this endogenous repair process is This article is an open access article generally low, leading to permanent deficits and functional impairments [7]. distributed under the terms and Here, we summarize the crucial functions of adult OPCs in the CNS, starting from conditions of the Creative Commons their ability to myelinate axons and to regenerate disrupted myelin after injury, necessary Attribution (CC BY) license (https:// to preserve efficient impulse conduction and trophic support to neurons. The reactivity of creativecommons.org/licenses/by/ these cells is also discussed based on recent data suggesting that their responsiveness to 4.0/). Cells 2021, 10, 565. https://doi.org/10.3390/cells10030565 https://www.mdpi.com/journal/cells Cells 2021, 10, 565 2 of 32 myelin damage is markedly dependent on their heterogeneity [8]. We also report recent evidence showing the capability of OPCs to sense and react to inflammation, playing a Cells 2021, critical10, x FOR PEER role REVIEW in the modulation of the immune-inflammatory response which accompanies2 of 33 many neurologicalthese diseases cells is also [9]. discussed In particular, based on we recent discuss data suggesting the role of that oligodendroglia their responsiveness in to ALS, based on a growingmyelin number damage is of markedly studies dependent revealing on thattheir OLheterogeneity injury is [8]. a crucialWe also report contributing recent factor ultimatelyevidence leading showing to neuronal the capability degeneration of OPCs to sense and and pathology react to inflammation, progression. playing Finally, a critical role in the modulation of the immune-inflammatory response which accompanies we highlight currentlymany neurological evaluated diseases drugs [9]. forIn particular, OL and we myelin discuss repair the role therapies of oligodendroglia that might in potentially serveALS, as therapeutic based on a growing approaches number of in studies ALS. revealing that OL injury is a crucial contrib- uting factor ultimately leading to neuronal degeneration and pathology progression. Fi- 2. Oligodendrocytenally, Functions we highlight in currently Adult evaluated CNS drugs for OL and myelin repair therapies that 2.1. Myelin Generationmight potentially and Remyelination serve as therapeutic approaches in ALS. Classically, the2. Oligodendrocyte primary and Functions most investigated in Adult CNS role attributed to OLs is to form myelin, a multilamellar fatty2.1. Myelin membrane, Generation mainly and Remyelination composed by glycosphingolipids and cholesterol, that enwraps axonsClassically, ensuring the their primary insulation and most andinvestigated the saltatory role attributed conduction to OLs is to of form nerve my- im- pulses [10] (Figureelin,1A). a multilamellar The formation fatty membrane, of myelin mainly is acomplex composed processby glycosphingolipids during which and cho- OPCs lesterol, that enwraps axons ensuring their insulation and the saltatory conduction of become mature OLsnerve through impulses a[10] highly (Figure regulated 1A). The format programion of ofmyelin differentiation is a complex process [11]. OPCs during are generated from radialwhich OPCs glia cellsbecome in mature multiple OLs through localized a hi areasghly regulated during program embryogenesis of differentiation [12–14 ]. In the developing[11]. murine OPCs are spinal generated cord, from OPCsradial glia initially cells in multiple arise around localized embryonicareas during embryo- day 12.5 (E12.5) in the ventralgenesis ventricular [12–14]. In the zone developing (VZ) murine and migrate spinal cord, all OPCs through initially the arise spinal around cord embry- before onic day 12.5 (E12.5) in the ventral ventricular zone (VZ) and migrate all through the spi- differentiating intonal cord myelin-forming before differentiating OLs into [15 myelin-forming,16]. Later, around OLs [15,16]. E15.5, Later, some around OPCs E15.5, some start to be generated inOPCs the dorsal start to be VZ, generated contributing in the dorsal 10–15% VZ, contributing of the final 10–15% OL of populationthe final OL popula- [12–14]. Regarding mousetion forebrain, [12–14]. Regarding three sequential mouse forebrain, waves three of sequential OPCs are waves generated of OPCs fromare generated different parts of the telencephalicfrom different VZ parts with of the a temporal telencephalic ventral-to-dorsal VZ with a temporal progressionventral-to-dorsal [17 progression]. [17]. Figure 1. Functions of oligodendrocyte (OL) lineage cells in the adult central nervous system (CNS). Oligodendrocyte precursorFigure cells 1. (OPCs)Functions become of mature oligodendrocyte and sustain myelinatio (OL) lineagen and remyelination cells in the during adult deve centrallopment nervous or in response system to (CNS). injuryOligodendrocyte (A). Mature myelinating precursor OLs release cells lactate (OPCs) produced become by glycolysis mature into and the sustainperiaxonal myelination space through andmonocarbox- remyelination ylateduring transporter development (MCT) 1. Neurons or in can response in turn take to up injury lactate (throughA). Mature the MCT2 myelinating to support mitochondrial OLs release ATP lactate synthesis produced by glycolysis into the periaxonal space through monocarboxylate transporter (MCT) 1. Neurons can in turn take up lactate through the MCT2 to support mitochondrial ATP synthesis (B). Finally, OPCs in the disease state are also known to express major histocompatibility complex (MHC) class I and II and several cytokines which enable them to modulate T-cells and microglia, thus affecting the immune response (C). In rodents, OPCs differentiate during the first two postnatal weeks, whereas in humans they mostly develop between 23 and 37 weeks of gestation [18] and CNS myelination Cells 2021, 10, 565 3 of 32 gradually increases in a defined topographic
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