Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target

Abstract

Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.

Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia

“…In our previous study, we demonstrated a decrease in ASMse activity in the blood of MSA patients [ 16 ]. Interestingly, a recent review discussed the abnormalities of the ASMase–ceramide signaling pathway in SCZ patients [ 45 ]. This review discusses that the aberrations in the ASMase/ceramide system, especially ASMase activity and the levels of ceramide, may alter the cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter dysfunction as dopamine neurotransmission and neuroinflammation [ 45 ].…”

“…However, earlier research has described a broad range of neurological manifestations also for NPD including severe ataxia, cognitive deficits, and psychiatric disorders [ 46 ]. Zhuo and coauthors suggested that normalization of the aberrant ASMase/ceramide system or ceramide reduction using approved functional inhibitors of ASMase, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of SCZ patients [ 45 ].…”

Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology

“…Peripherally, aberrant alterations in sphingomyelin and ceramide levels in the red blood cells and skin are strongly linked to schizophrenia [ 50 ]. It has even been hypothesized that the disruption of the acid sphingomyelinase/ceramide system contributes to the dopamine neurotransmission malfunction, neuroinflammation, and oxidative stress, which are the main theories regarding the cause of schizophrenia [ 12 ]. Interestingly, PSAP plays a fundamental role in the sensitization of neurons to oxidative stress [ 8 ], and PGRN is also a neuroinflammation modulator [ 35 ].…”

“…PSAP mutations are linked to Parkinson’s disease (PD) [ 10 ], and an association of single nucleotide polymorphisms (SNPs) in the PSAP gene with schizophrenia was revealed in a Dutch population [ 11 ]. Meanwhile, as the main substrate of saposins, sphingolipid metabolism is abnormal in patients with schizophrenia [ 12 ].…”

Nutritional roles and therapeutic potentials of dietary sphingomyelin in brain diseases

“…This reduction shown in other studies was speculated to be the result of SCZ-associated upregulation in S1P-degrading enzymes genes. ( 45 )…”