biomolecules Review The Multiple Roles of Sphingomyelin in Parkinson’s Disease Paola Signorelli 1 , Carmela Conte 2 and Elisabetta Albi 2, *   Citation: Signorelli, P.; Conte, C.; Albi, E. The Multiple Roles of Sphingomyelin in Parkinson’s Disease. Biomolecules 2021, 11, 1311. https://doi.org/10.3390/ biom11091311 Academic Editor: Robert V. Stahelin Received: 5 August 2021 Accepted: 3 September 2021 Published: 5 September 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, 20142 Milan, Italy; paola.signorelli@unimi.it 2 Department of Pharmaceutical Sciences, University of Perugia, 06126 Perugia, Italy; carmela.conte@unipg.it * Correspondence: elisabetta.albi@unipg.it 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 1. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disease (ND) after Alzheimer’s disease (AD). Recent breakthroughs in our knowledge of the molecular mechanisms underlying PD involve unfolded protein responses and protein aggregation. 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 (α-Syn). [1]. As a consequence, neurons undergo degeneration. The degenerative mecha- nism in reality is complex. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and lysosomal dysfunction have been called into question [2]. Recently, a lot of atten- tion has been given to lysosomes. They are fascinating organelles known in the past 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- dependent signal transduction [3]. Due to all these functions, lysosomes maintain neuronal homeostasis in the brain. Thus, their dysfunction underlies NDs, especially PD. In fact, several genes and/or genetic risk factors linked to PD encode for lysosomal proteins. Thus, 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 and lysosomal sphingolipid (Sph) metabolism defects [5]. Rare genetic diseases due the intralysosomal accumulation of Sphs due to the defect of their degradation are called lyso- somal storage diseases (LSD). They include gangliosidoses, Krabbe disease, Fabry disease, Farber disease, Gaucher disease, Niemann-Pick disease (characterized by accumulation of gangliosides) (GM), galactosylceramide (GalCer), trihexosyl ceramide (TrihexosylCer), ceramide (Cer), glucosylceramide (GCer) and sphingomyelin (SM). During the last ten years, epidemiologic and biochemical evidence has brought to our attention a link between Biomolecules 2021, 11, 1311. https://doi.org/10.3390/biom11091311 https://www.mdpi.com/journal/biomolecules