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Implications in Parkinson's Disease Journal of Clinical Medicine Review Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease Silvia Paciotti 1,2 , Elisabetta Albi 3 , Lucilla Parnetti 1 and Tommaso Beccari 3,* 1 Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy; [email protected] (S.P.); [email protected] (L.P.) 2 Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Sant’Andrea delle Fratte, 06132 Perugia, Italy 3 Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy; [email protected] * Correspondence: [email protected] Received: 29 January 2020; Accepted: 20 February 2020; Published: 21 February 2020 Abstract: Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson’s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson’s disease. Keywords: ceramide metabolism; Parkinson’s disease; α-synuclein; GBA; GLA; HEX A-B; GALC; ASAH1; SMPD1; ARSA * Correspondence [email protected] 1. Introduction Ceramides (Cers) are a family of bioactive lipids belonging to the class of sphingolipids (SphLs). Cers differ in their fatty acid composition (medium chain (C12–C14), long chain (C16–C18), very-long chain (C20–C24), and ultra-long chain ( C26) and in their saturation state. In the past, Cers were known ≥ only as structural lipids and advances over the past decade have opened new horizons. It has been proposed that different Cer species are involved in physiological and pathological cellular processes (e.g., inflammation [1], cell proliferation, differentiation, apoptosis, and cancer) depending on their ability to influence membrane properties and interact with effector proteins [2], and play a role in neurodegeneration [3]. Stith et al. [2] have highlighted new faces of Cers discovered thanks to the generation and characterization of KO mice for the ceramide-metabolizing enzyme, as well as for the identification of their specific inhibitors and antibodies, and to the design of synthetic Cer derivates. Thus, in the time, Cers, the enzymes for their metabolism, and consequently their derivates have been better understood as possible diagnostic markers and as drug targets for innovative therapeutic strategies. This review provides evidence into the role of ceramide metabolism in the physiopathology of lysosomes, highlighting recent findings on its involvement in Parkinson’s disease (PD). J. Clin. Med. 2020, 9, 594; doi:10.3390/jcm9020594 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 594 2 of 20 J. Clin. Med. 2020, 9, 594 2 of 19 2.2. Interplay ofof Ceramides Ceramides and and Lipid Lipid Containing Containing Ceramides Ceramides between between Lysosomes Lysosomes and Other and Other CellularCellular Compartments Compartments CersCers residereside in in di ffdifferenterent cellular cellular compartments compartmen (Figurets (Figure1). They 1). are They synthesized are synthesized in the endoplasmic in the endoplasmicreticulum and reticulum processed and in processed the Golgi in apparatus the Golgi toapparatus form sphingomyelin to form sphingomyelin (SM) and (SM) more and complex more complexSphLs, the SphLs, glycolsphingolipids the glycolsphingolipids (GSLs)[ 4(GSLs)]. Cer, [4]. SM, Cer, and SM, GSLs and are GSLs then are distributed then distributed in all cellular in all cellularcompartments compartments with di withfferent differ specificent specific destinies destinies and roles. and roles. In the In plasma the plasma membrane, membrane, Cers Cers are both are bothrandomly randomly distributed distributed and locatedand located in specific in specific structures structures called called lipid lipid rafts rafts [5]. [5]. They They are are responsible responsible for forthe the normally normally existing existing lipid lipid asymmetry asymmetry by influencing by influencing the mechanical the mechanical stability stability of the membraneof the membrane [4], and [4],for theand structure for the structure and regulation and regulation of lipid rafts of [lipid6]. In rafts the inner[6]. In nuclear the inner membrane, nuclear theymembrane, are concentrated they are concentratedin lipid microdomains, in lipid microdomains, where they regulate where thethey active regulate chromatin the active function chromatin [7]. Cellular function membrane [7]. Cellular Cer membranecan derive Cer from can SM derive directly from in locoSM directly but also in from loco SM but and also GSLs from afterSM and a more GSLs complex after a more mechanism complex of mechanismdegradation. of In degradation. fact, while proteins, In fact, glycoproteins, while proteins, or oligosaccharidesglycoproteins, or can oligosaccharides be degraded by can soluble be degradedenzymes inby di solublefferent enzymes cell sites, in the different degradation cell sites, of membrane the degradation SM and of GSLs membrane requires SM a much and GSLs more requirescomplex a catabolic much more system complex that occurs catabolic in lysosomes system th [at8,9 occurs]. Thus, in membrane lysosomes fractions, [8,9]. Thus, containing membrane SM fractions,and GSLs, containing reach lysosomes SM and by GSLs, the endocytic reach lysoso vesicularmes flow,by the through endocytic the early vesicular and late flow, endosome through from the earlythe Golgi and late apparatus endosome [10]. from After the reaching Golgi apparatus the lysosomes, [10]. CersAfter produced reaching fromthe lysosomes, SM and GSL Cers degradation, produced fromandmetabolism SM and GSL intermediates degradation, are and continuously metabolism recycled intermediates and re-utilized are continuously in salvage recycled processes and [10 ,11re-]. utilizedIn particular, in salvage Cer, fatty processes acids, [10,11]. and sugar In particular, are exported Cer, from fatty the acids, lysosomes and sugar through are specificexported membrane from the lysosomesproteins and through reach again specific the membrane Golgi apparatus proteins where and they reach are again recycled the into Golgi the apparatus biosynthetic where pathway they [are11]. recycledEven if very into little the isbiosynthetic known about pathway this mechanism [11]. Even of transport,if very little it is is well known known about as an this interplay mechanism between of transport,lysosomes it and is well plasma known membrane as an /interplaycellular organellesbetween lysosomes by processes andof plasma membrane membrane/ fusions, cellular which organellescould be responsible by processes for of the membrane shift of GSL fusions, from which one cellular could compartmentbe responsible to for another. the shift Ultrastructural of GSL from oneexamination cellular compartment of cells, from to patients another. with Ultrastructural defects of GSLexamination degradation, of cells, highlighted from patients accumulation with defects of ofnon-degradable GSL degradation, lipids highlighted in multi-vesicular accumulation storage of bodies, non-degradable that are responsible lipids in multi-vesicular for different diseases storage in bodies,relation that with are the responsible implicated for enzymes. different diseases in relation with the implicated enzymes. Figure 1. Schematic representation of the interplay between lysosomes and other cellular compartments of ceramides and lipids containing ceramides. Description in the text. ER, endoplasmic reticulum; GA, FigureGolgi apparatus;1. Schematic INM, representation inner nuclear membrane; of the interpla L, lysosome;y between LR, lipid lysosomes raft; PM, plasmaand other membrane. cellular compartments of ceramides and lipids containing ceramides. Description in the text. ER, endoplasmic reticulum; GA, Golgi apparatus; INM, inner nuclear membrane; L, lysosome; LR, lipid raft; PM, plasma membrane. J. Clin. Med. 2020, 9, 594 3 of 19 3. Ceramide Metabolism in Cell Membranes Cer is the heart of SphL metabolism. It is produced in cells through three pathways: de novo synthesis, sphingosine (Sph) reacylation (salvage pathway), and breakdown of SM [12] and it is used to form other simple SphLs as SM, Cer-1-phosphate (Cer1P), Sph, and consequently, Sph-1-phosphate (S1P) and GSLs (Figure 2). The novo synthesis starts from the condensation of an activated fatty acid (palmitoyl-CoA) and an amino acid (serine) by serine palmitoyl-CoA acyltransferase to form 3- dehydro-D-sphinganine that is reduced to sphinganine (also called dihydrosphingosine) and acetylated to N-acylsphinganine (also called dihydroceramide) by Cer synthase (CerS) and finally reduced to Cer. The breakdown of Cer by ceramidase (Cerase) results in the formation
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