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The Multiple Roles of Sphingomyelin in Parkinson's Disease

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The Multiple Roles of Sphingomyelin in Parkinson's Disease biomolecules Review The Multiple Roles of Sphingomyelin in Parkinson’s Disease Paola Signorelli 1 , Carmela Conte 2 and Elisabetta Albi 2,* 1 Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, 20142 Milan, Italy; [email protected] 2 Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy; [email protected] * Correspondence: [email protected] Abstract: Advances over the past decade have improved our understanding of the role of sphin- golipid in the onset and progression of Parkinson’s disease. Much attention has been paid to ceramide derived molecules, especially glucocerebroside, and little on sphingomyelin, a critical molecule for brain physiopathology. Sphingomyelin has been proposed to be involved in PD due to its presence in the myelin sheath and for its role in nerve impulse transmission, in presynaptic plasticity, and in neurotransmitter receptor localization. The analysis of sphingomyelin-metabolizing enzymes, the development of specific inhibitors, and advanced mass spectrometry have all provided insight into the signaling mechanisms of sphingomyelin and its implications in Parkinson’s disease. This review describes in vitro and in vivo studies with often conflicting results. We focus on the synthesis and degradation enzymes of sphingomyelin, highlighting the genetic risks and the molecular alterations associated with Parkinson’s disease. Keywords: sphingomyelin; sphingolipids; Parkinson’s disease; neurodegeneration Citation: Signorelli, P.; Conte, C.; 1. Introduction Albi, E. The Multiple Roles of Sphingomyelin in Parkinson’s Parkinson’s disease (PD) is the second most common neurodegenerative disease (ND) Disease. Biomolecules 2021, 11, 1311. after Alzheimer’s disease (AD). Recent breakthroughs in our knowledge of the molecular https://doi.org/10.3390/ mechanisms underlying PD involve unfolded protein responses and protein aggregation. biom11091311 Of note, dopaminergic neuronal cells of the substantia nigra suffer from an abnormal accumulation and aggregation of a specific presynaptic neuronal protein, the α-synuclein Academic Editor: Robert V. Stahelin (α-Syn). [1]. As a consequence, neurons undergo degeneration. The degenerative mecha- nism in reality is complex. Mitochondrial dysfunction, oxidative stress, neuroinflammation, Received: 5 August 2021 and lysosomal dysfunction have been called into question [2]. Recently, a lot of atten- Accepted: 3 September 2021 tion has been given to lysosomes. They are fascinating organelles known in the past Published: 5 September 2021 for being the recycling centers of the cell and recently considered essential to mediate metabolic adaptation, to control the functionality of organelles, and to regulate nutrient- Publisher’s Note: MDPI stays neutral dependent signal transduction [3]. Due to all these functions, lysosomes maintain neuronal with regard to jurisdictional claims in homeostasis in the brain. Thus, their dysfunction underlies NDs, especially PD. In fact, published maps and institutional affil- several genes and/or genetic risk factors linked to PD encode for lysosomal proteins. Thus, iations. PD-associated gene mutation is associated with lysosomal impairment. Because α-Syn degradation occurs in lysosomes, their dysfunction affects α-Syn turnover causing an unavoidable increase in its intracellular levels, leading to its accumulation and aggregation in tissues [4]. Studies spanning two decades have revealed the association between PD Copyright: © 2021 by the authors. and lysosomal sphingolipid (Sph) metabolism defects [5]. Rare genetic diseases due the Licensee MDPI, Basel, Switzerland. intralysosomal accumulation of Sphs due to the defect of their degradation are called lyso- This article is an open access article somal storage diseases (LSD). They include gangliosidoses, Krabbe disease, Fabry disease, distributed under the terms and Farber disease, Gaucher disease, Niemann-Pick disease (characterized by accumulation conditions of the Creative Commons of gangliosides) (GM), galactosylceramide (GalCer), trihexosyl ceramide (TrihexosylCer), Attribution (CC BY) license (https:// ceramide (Cer), glucosylceramide (GCer) and sphingomyelin (SM). During the last ten creativecommons.org/licenses/by/ years, epidemiologic and biochemical evidence has brought to our attention a link between 4.0/). Biomolecules 2021, 11, 1311. https://doi.org/10.3390/biom11091311 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 2 of 14 During the last ten years, epidemiologic and biochemical evidence has brought to our attention a link between Gaucher disease, caused by a deficiency of glucocerebrosidase (GBA), which is useful for degrading GCer, and PD. GBA variants predispose individuals Biomolecules 2021, 11, 1311 2 of 14 to αSyn accumulation and neurodegeneration even in the heterozygous status [6]. Of note, GCer accumulation promotes the conversion of αSyn into a proteinase K‐resistant confor‐ mation [7]. Recently, it has been demonstrated that inhibition of Cer synthesis reduces Gaucher disease, caused by a deficiency of glucocerebrosidase (GBA), which is useful αSyn accumulationfor [8]. degrading GCer, and PD. GBA variants predispose individuals to αSyn accumulation While there isand a plethora neurodegeneration of information even in about the heterozygous the relation status between [6]. Of note,Cer and GCer PD, accumulation there is also a dearth ofpromotes knowledge the conversion about the of αinvolvementSyn into a proteinase of SM K-resistant in PD. However, conformation in [ 7recent]. Recently, years, the field thatit has studies been demonstrated the roles of that SM inhibition in the ofbrain Cer synthesishas made reduces importantαSyn accumulation strides in [8]. While there is a plethora of information about the relation between Cer and PD, there understanding theis different also a dearth ways of knowledgeSM can regulate about the brain involvement physiopathology. of SM in PD. However, in recent In this review,years, we will the field explore that studies the different the roles behavior of SM in the of SM brain and has SM made metabolism important strides en‐ in zymes in PD from understandinggene risk to lipid the different and enzyme ways SM modifications. can regulate brain physiopathology. In this review, we will explore the different behavior of SM and SM metabolism 2. Sphingomyelinenzymes Metabolism in PD from gene risk to lipid and enzyme modifications. SM is synthesized2. Sphingomyelin by SM‐synthase Metabolism using both phosphatidylcholine (PC) as donor of a phosphorylcholine groupSM is synthesized and free byCer. SM-synthase It is catabolized using both to phosphatidylcholine Cer by sphingomyelinase (PC) as donor of (SMase). Cer in turna phosphorylcholine can be metabolized group andvia free different Cer. It ispathways: catabolized (1) to Cerit is by degraded sphingomyelinase by (SMase). Cer in turn can be metabolized via different pathways: (1) it is degraded by ceramidase (Cerase),ceramidase producing (Cerase), sphingosine producing (SP) sphingosine that can (SP) be thatphosphorylated can be phosphorylated by sphingo by sphin-‐ sine kinase (SphK)gosine to form kinase sphingosine (SphK) to‐ form1‐phosphate sphingosine-1-phosphate (S1P); (2) it is (S1P);complexed (2) it is with complexed sugar with molecules to formsugar GCer molecules and GalCer to form GCerby GCer and GalCer‐synthase by GCer-synthase (GCerS) and (GCerS) GalCer and GalCer-synthase‐synthase (GalCerS), respectively;(GalCerS), (3) respectively;it is used to (3) form it is used more to formcomplex more complexmolecules, molecules, the ganglioside the ganglioside (GM). GCer and GalCer can be degraded by GBA or galactocerebrosidase (GalBA), freeing (GM). GCer and GalCer can be degraded by GBA or galactocerebrosidase (GalBA), freeing Cer and glucose (G) or galactose (Gal), respectively (Figure1) Cer and glucose (G) or galactose (Gal), respectively (Figure 1) GM Figure 1. Sphingomyelin metabolism in the brain. Description in the text. SM, sphingomyelin; PC, phosphatidylcholine; Cer,Figure ceramide; 1. SMase, Sphingomyelin sphingomyelinase; metabolism Cerase, ceramidase; in the brain. SphK, Description sphingosine in kinase; the text. SP, sphingosine, SM, sphingomyelin; S1P, sphingosine- PC, 1-phosphate;phosphatidylcholine; GCerS, glucosylceramide Cer, ceramide; synthase; SMase, GalCerS, sphingomyelinase; galactosylceramide synthase; Cerase, GCer, ceramidase; glucosylceramide; SphK, GalCer,sphin‐ galactosylceramide;gosine kinase; GBA,SP, sphingosine, glucocerebrosidase; S1P, GalBAsphingosine galactocerebrosidase;‐1‐phosphate; G, glucose;GCerS, Gal,glucosylceramide galactose.; GM, ganglioside. synthase; TheGalCerS, yellow arrows galactosylceramide indicate the metabolic synthase; syntheses; GCer, the amaranth glucosylceramide; red arrows represent GalCer, the galactosylceramide; production of Cer from GBA, SM andglucocerebrosidase; its utilization; the green GalBA arrows indicategalactocerebrosidase; enzymes with degradation G, glucose; function Gal, andgalactose.; the orange GM, arrow ganglioside. an enzyme with The phosphorylationyellow arrows function; indicate the purple the metabolic arrows indicate syntheses; the effect the of GBA amaranth and GalBA, red i.e., arrows production represent of Cer andthe Gproduction or Gal; the blueof arrow Cer indicatesfrom SM the and use ofits Cer utilization; to synthesise the GM. green arrows indicate enzymes with degradation function and the orange arrow
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