Role of sphingomyelinases in neurological disorders

Abstract

More research needs to be carried out to develop pharmacological agents that act on sphingomyelinases, for the prevention or treatment of neurological disorders.

Doxepin Mitigates Noise‐induced Neuronal Damage in Primary Auditory Cortex of Mice via Suppression of Acid Sphingomyelinase/Ceramide Pathway

“…It has been well known that the Niemann‐Pick type A disease arises from ASM gene deficiency which induces accumulation of SM, cholesterol, glycosphingolipids, and bis‐(monoacylglycerol) phosphate in encephalon tissue or visceral organs evoking hepatosplenomegaly, pulmonary insufficiency, and cardiovascular disease (Schuchman and Wasserstein, ). However, over‐activated ASM induced excessive Cer generation is pernicious as well for promoting inflammation, apoptosis and oxidation which underlies a wide range of neuronal disorders such as depression (Kornhuber et al, ), Alzheimer's dementia, Parkinson's disease, Huntington's chorea, cerebral ischemia, and pain (Ong et al, ). Inhibition of ASM/Cer pathway has shown evident advantages in neurogenesis, neuronal stabilization, maturation and survival (Gulbins et al, ).…”

“…Acid sphingomyelinase (ASM), acid ceramidase (AC), and ceramide (Cer) are three essential components of sphingolipids (SLs) (Ong et al, ). ASM catalyzes sphingomyelin (SM) breakdown into Cer and AC Cer into sphingosine, which mainly work in the acidic condition of endo/lysosomal compartments (Gault et al, ).…”

“…Proper ASM activity is crucial, with deficiency of its gene leading to accumulation of SM, cholesterol, glycosphingolipids, and bis‐(monoacylglycerol) phosphate within lysosomes which is the pathogenesis of Niemann‐Pick type A disease and severe other neuronal degenerations (Schuchman and Wasserstein, ). However, over‐activated ASM induces extra production of Cer which is detrimental as well for accelerating inflammation, apoptosis and accrual of oxidative stress underlying neurological maladies such as major depression (Kornhuber et al, ), Alzheimer's disease (Xuan et al, ), cerebral ischemia (Yu et al, ), and pain (Ong et al, ). Given the situation, medication aimed to reduce ASM activity has shown high efficiency in recovering neurogenesis and restoring neuronal network (Beckmann et al, ; Gulbins et al, ).…”

Activation of Liver X receptors (LXRs) increases sphingolipid biosynthesis in hepatic cells.

“…Sphingolipids are bioactive lipid molecules that have been implicated as key modulators of many diseases including cardiovascular, metabolic and autoimmune, and neurological disorders [1]. Of the many classes of sphingolipids, ceramide and sphingosine-1-phosphate have been shown to be an important mediators in the cellular signal transduction involved in apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation in multiple tissues [2] [3] [4] [5] [6]. Understanding the complex regulation of sphingolipid synthesis would help to identify key ceramide, biosynthetic, and degradation pathways as potential pharmacological targets.…”

Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A

“…Hydrolysis of sphingomyelin (SM) 3 to ceramide and phosphocholine by sphingomyelinase enzymes (SMases) alters membrane properties and can result in the formation of signaling platforms, thus facilitating signal transduction (1). Mammalian SMases are classified into three categories based on their pH optimum (2). The lone alkaline SMase metabolizes SM in the intestinal tract (3), whereas neutral SMases are active on the cytosolic side of the plasma membrane and in various organelles (4).…”