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Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?

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Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? biomolecules Review Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? Rosa Manzoli 1,2,†, Lorenzo Badenetti 1,3,4,†, Michela Rubin 1 and Enrico Moro 1,* 1 Department of Molecular Medicine, University of Padova, 35121 Padova, Italy; [email protected] (R.M.); [email protected] (L.B.); [email protected] (M.R.) 2 Department of Biology, University of Padova, 35121 Padova, Italy 3 Department of Women’s and Children’s Health, University of Padova, 35121 Padova, Italy 4 Pediatric Research Institute “Città della Speranza”, 35127 Padova, Italy * Correspondence: [email protected]; Tel.: +39-04-98276341 † These authors contributed equally to this paper. Abstract: Axonal trajectories and neural circuit activities strongly rely on a complex system of molec- ular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely un- derstood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases. Citation: Manzoli, R.; Badenetti, L.; Keywords: axon guidance; lysosomal storage disorders; neuronal circuit Rubin, M.; Moro, E. Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? Biomolecules 2021, 11, 191. 1. Introduction https://doi.org/10.3390/ biom11020191 The development of the central nervous system (CNS) occurs during embryonic stages in a strictly temporally and spatially regulated manner, to allow for the organization of Academic Editor: Vladimir a network of nervous fibers that progressively increase the range of functional neuronal N. Uversky interactions. The high degree of complexity is achieved through a balanced and controlled Received: 4 January 2021 process of axonal remodeling, followed by the formation of specific synapses that cross- Accepted: 26 January 2021 connect target neuronal populations in order to establish a dynamic system of integrated Published: 29 January 2021 communication [1,2]. Axonal remodeling involves the elimination of “useless” connections and the formation and growth of new dendritic spines and axonal trajectories that enable Publisher’s Note: MDPI stays neutral brain plasticity and correct sensory responses to external stimuli. Impaired axonal remod- with regard to jurisdictional claims in eling and pathfinding lead to defective synaptic connectivity and aberrant neuronal circuit published maps and institutional affil- function, which characterize both congenital disorders and neurodegenerative conditions. iations. While we know which extrinsic factors (that is, environmental stimuli, injury, and neuronal activity) may govern the ability to increase the axonal branching and pruning [3], we do not have a clear picture of which intrinsic factors (genetically encoded proteins, type of cell population) finely modulate the overall setting of the neuronal network during early em- Copyright: © 2021 by the authors. bryogenesis. In addition, we still lack extensive knowledge of whether and how in certain Licensee MDPI, Basel, Switzerland. cases (for instance, brain injuries and traumatic insults) axonal regeneration takes place This article is an open access article and which molecules control this process. Understanding the cascade of molecular events distributed under the terms and occurring during both embryonic brain development and after brain injury could allow conditions of the Creative Commons for the identification of druggable targets that may hamper neurodegenerative conditions Attribution (CC BY) license (https:// and prevent the onset of irreversible cognitive decline in certain inherited disorders. In creativecommons.org/licenses/by/ the past few years, lysosomes have attracted a remarkable interest for their key role in the 4.0/). Biomolecules 2021, 11, 191. https://doi.org/10.3390/biom11020191 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 191 2 of 14 Biomolecules 2021, 11, 191 identification of druggable targets that may hamper neurodegenerative2 of 13conditions and prevent the onset of irreversible cognitive decline in certain inherited disorders. In the past few years, lysosomes have attracted a remarkable interest for their key role in the autophagic process during axonal remodeling [4]. Besides, many lysosomal enzyme autophagic processdefects during have axonalbeen detected remodeling in [4neurodegener]. Besides, manyative lysosomal conditions enzyme [5]. A defects few years ago, a have been detectedpioneering in neurodegenerative study revealed a conditionstight association [5]. A fewbetween years ago,lysosomal a pioneering activity and axonal study revealedpruning a tight association[6]. More recently, between lysosomalFarfel-Becker activity and andcolleagues axonal pruning demonstrated [6]. More that lysosomes recently, Farfel-Beckerare actively and delivered colleagues to demonstrated the distal termini, that lysosomes suggesting are their actively pivotal delivered function in axonal to the distal termini, suggesting their pivotal function in axonal dynamics [7]. Therefore, dynamics [7]. Therefore, an emerging role of lysosomal activity in axon growth and an emerging role of lysosomal activity in axon growth and guidance is gaining attention, guidance is gaining attention, positing lysosomes as one of the top interests of positing lysosomes as one of the top interests of neurobiologists. In this review, we will try neurobiologists. In this review, we will try to briefly summarize the current knowledge of to briefly summarize the current knowledge of up-to-date discovered axonal guidance cues, up-to-date discovered axonal guidance cues, providing an inferential nexus between providing an inferential nexus between their impaired activity and the brain pathogenesis their impaired activity and the brain pathogenesis of lysosomal storage disorders (LSDs). of lysosomal storage disorders (LSDs). 2. Axonal Guidance2. Axonal Cues Guidance Cues The term “axonThe guidance” term “axon refers guidance” to all mechanisms refers to all thatmechanisms allow a developing that allow a axon developing to axon to elongate fromelongate the neuronal from soma the neuronal and reach soma its target and tissues. reach its A nascenttarget tissues. axonal growthA nascent cone axonal growth can indeed integratecone can and indeed transduce integrate a multitude and transduce of different a multit stimuliude of itdifferent receives stimuli from the it receives from surrounding extracellularthe surrounding environment. extracellular This resultsenvironment. in precise This and results predictable in precise shaping and of predictable axonal routesshaping in the developing of axonal nervous routes system.in the Thedevelopin strikingg conceptnervous of system. axonal pathfindingThe striking concept of has traveled alongaxonal centuries, pathfinding from has Ram traveledón y Cajal along and centuries, his studies from of theRamón embryonic y Cajal chickand his studies of spinal cord (1890),the embryonic to the identification chick spinal and cord characterization (1890), to the ofidentification axon guidance and cues’characterization major of axon families (i.e., netrins,guidance slits, cues’ semaphorins, major families and (i.e., ephrins), netrins, together slits, semaphorins, with morphogens, and ephrins), growth together with factors, glycoproteins,morphogens, and cellgrowth adhesion factors, molecules glycoproteins, (CAMs) [and8]. Axon cell adhesion guidance moleculesmolecules (CAMs) [8]. can be dividedAxon into guidance attractive molecules and repulsive can be cuesdivided that into act a eitherttractive diffusively and repulsive over cues long that act either distances or locally,diffusively in a contact-dependent over long distances manner. or locally, Cooperation in a contact-dependent between long-range manner. and Cooperation short-range guidancebetween cueslong-range is required and for short-range the navigation guidance of growing cues is axons required to their for target the navigation of cells (Figure1).growing axons to their target cells (Figure 1). Figure 1. AxonFigure guidance 1. Axon cues guidance and endo-lysosom cues and endo-lysosomalal pathway in pathway the axonal in thegrowth axonal cone. growth A schematic cone. A schematicpicture depicts the modular structurepicture of depicts major axonal the modular guidance structure cue-related of major receptors axonal and guidance their respective cue-related ligands. receptors Classical and interactions their are represented byrespective black arrows, ligands. while Classical red arro interactionsws indicate are crosstalk represented between by black different arrows, axon while guidance red arrows families. indicate In the bottom crosstalk between different axon guidance families. In the bottom part of the figure, the endosomal– lysosomal compartment is shown to mediate both receptor recycling and degradation. (created with BioRender.com). Biomolecules 2021, 11, 191 3 of 13 2.1. Semaphorins Semaphorins (SEMAs), first described in 1992 as
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