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The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair After CNS Injury and Disease

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The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair After CNS Injury and Disease cells Review The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease Debasish Roy 1 and Andrea Tedeschi 1,2,* 1 Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; [email protected] 2 Discovery Theme on Chronic Brain Injury, The Ohio State University, Columbus, OH 43210, USA * Correspondence: [email protected] Abstract: Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon Citation: Roy, D.; Tedeschi, A. The regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid Role of Lipids, Lipid Metabolism and accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and after CNS Injury and Disease. Cells non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and 2021, 10, 1078. https://doi.org/ disease. 10.3390/cells10051078 Keywords: lipids; axon growth and regeneration; mitochondria transport; myelin formation; adipose Academic Editor: tissue; CNS trauma and disease Antón Barreiro-Iglesias Received: 23 March 2021 Accepted: 27 April 2021 1. Introduction Published: 1 May 2021 Developing axons in the mammalian nervous system can extend very long dis- tances [1]. After reaching their targets, axons integrated into functional circuits continue to Publisher’s Note: MDPI stays neutral extend via mechanisms of stretch growth as the body continues to grow [2,3]. Continuous with regard to jurisdictional claims in addition of new axonal membrane is necessary to fuel axon growth during development as published maps and institutional affil- well as long distance axon regeneration in adulthood [4–6]. Similarly, complex dendritic iations. growth and myelin formation also require large amounts of membrane. Phospholipids, glycolipids and cholesterol constitute the major kinds of membrane lipids [7] (Figure1) . Phospholipids are the most abundant and are generally composed of two fatty acids that can differ in length and a phosphate group attached to a glycerol backbone [8]. Due to Copyright: © 2021 by the authors. their shape and amphipathic nature, phospholipids spontaneously aggregate to form bi- Licensee MDPI, Basel, Switzerland. layers in aqueous environments. Made of a hydrophobic lipid tail and one or more sugar This article is an open access article groups linked by a glycosidic bond, glycolipids are found on the outer leaflet of eukaryotic distributed under the terms and cell membranes where they confer membrane stability and facilitate cell–cell communica- conditions of the Creative Commons tion and signal transduction. By making the lipid bilayer less deformable and less fluid, Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ cholesterol integration alters the permeability-barrier properties of the cellular membranes. 4.0/). Membrane proteins tend to accumulate within specialized microdomains of the plasma Cells 2021, 10, 1078. https://doi.org/10.3390/cells10051078 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 23 Cells 2021, 10, 1078 membranes. Membrane proteins tend to accumulate within specialized microdomains2 of 23 of the plasma membrane called lipid rafts that are rich in cholesterol and sphingolipids. Whereas axons in the mammalian peripheral nervous system spontaneously regenerate overmembrane long distances called lipid [9,10], rafts axons that are in rich the in cent cholesterolral nervous and sphingolipids.system (CNS) Whereas fail to mount ax- a suc- cessfulons in regenerative the mammalian response peripheral [11–13]. nervous Axon system regeneration spontaneously failure regenerate causes over long long term struc- turaldistances and functional [9,10], axons impairment in the central after nervous a variety system of CNS (CNS) trauma fail to mount including a successful brain and spinal cordregenerative injury (SCI) response [14,15]. [11–13 Previous]. Axon regeneration work has failuredemonstrated causes long that term accumulation structural and of certain functional impairment after a variety of CNS trauma including brain and spinal cord injury lipids(SCI) and [14,15 dysregulation]. Previous work of haslipid demonstrated metabolism that not accumulation only contribute of certain to developmental lipids and disor- dersdysregulation [16,17], axon of lipid growth metabolism and regeneration not only contribute failure to developmentalafter CNS trauma disorders [6,18], [16 ,but17], also neu- rodegenerativeaxon growth and diseases regeneration [19,20]. failure Lipids after CNSare also trauma implicated [6,18], but in also myelin neurodegenerative formation and serve asdiseases bioactive [19 ,molecules20]. Lipids and are also energy implicated substrates in myelin [21,22]. formation Here, we and discuss serve as classical bioactive and novel rolesmolecules of lipids, and energylipid metabolism substrates [21 ,and22]. Here,ectopic we discusslipid accumulation classical and novel in axon roles of growth/regener- lipids, ationlipid and metabolism CNS repair. and ectopic In addition, lipid accumulation we outline in molecular axon growth/regeneration and pharmacological and CNS strategies repair. In addition, we outline molecular and pharmacological strategies that fine tune thatlipid fine composition tune lipid and composition metabolism in and neurons metabo and non-neuronallism in neurons cells to and favor non-neuronal neurological cells to favorrecovery neurological after CNS traumarecovery and after disease. CNS trauma and disease. Figure 1. Lipids and plasma membrane. (A) Schematic representation of the three major kinds of Figuremembrane 1. Lipids lipids. and (B) Illustrationplasma membrane. of the typical (A lipid) Schematic bilayer of representation the plasma membrane. of the three major kinds of membrane lipids. (B) Illustration of the typical lipid bilayer of the plasma membrane. 2. Membrane Expansion 2. MembraneContinuous Expansion addition of new membrane is required during axon and dendrite growth [23,24], stretch growth of integrated axons [3] and axon regeneration [6,25–27] (Figure2). Newly synthesizedContinuous lipids addition for membrane of new expansion membrane are anterogradelyis required during transported axon and to the dendrite distal growth [23,24],axonal stretch compartment growth via of lipid integrated containing axons vesicles, [3] enablingand axon rapid regeneration elongation of[6,25–27] growing (Figure 2). Newlyaxons synthesized [5,23,27–29]. Inlipids addition, for membrane axons can locally expansion synthesize are anterogradely lipids, such as thetransported major to the distalmembrane axonal phospholipid compartment phosphatidylcholine via lipid containing [27]. Cholesterol vesicles, can enabling also be suppliedrapid elongation via of growing axons [5,23,27–29]. In addition, axons can locally synthesize lipids, such as the major membrane phospholipid phosphatidylcholine [27]. Cholesterol can also be sup- plied via uptake of lipoprotein particles during rapid membrane biogenesis. Along this line, low-density lipoprotein receptors have been found to densely cluster at the tip of Cells 2021, 10, 1078 3 of 23 Cells 2021, 10, x 3 of 23 uptake of lipoprotein particles during rapid membrane biogenesis. Along this line, low- peripheraldensity lipoproteinaxons during receptors regeneration have been[30]. Large found amounts to densely of clusterlipid supply at the are tip also of peripheral neces- saryaxons during during myelin regeneration growth and [30 repair]. Large [31 amounts–34] (Figure of lipid 2). supply are also necessary during myelin growth and repair [31–34] (Figure2). Figure 2. Membrane expansion during nervous system development and repair. Figure 2. Membrane expansion during nervous system development and repair. A schematic representation of membrane expansion during axonal and dendritic growth,A schematic stretch representation growth of integrated of membrane axons, myelin expansion formation during and axonal repair, and sealing dendritic of mem- growth,brane stretch ruptures growth and axon of integrated regeneration. axons, PPV: myelin plasmalemmal formation and precursor repair, vesicles.sealing of mem- brane ruptures and axon regeneration. PPV: plasmalemmal precursor vesicles. 2.1. Axon Growth & Regeneration 2.1. AxonMembrane
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