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 me...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-01999-7 |
| _version_ | 1818218722534359040 |
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| author | Chuanjun Zhuo Feifei Zhao Hongjun Tian Jiayue Chen Qianchen Li Lei Yang Jing Ping Ranli Li Lina Wang Yong Xu Ziyao Cai Xueqin Song |
| author_facet | Chuanjun Zhuo Feifei Zhao Hongjun Tian Jiayue Chen Qianchen Li Lei Yang Jing Ping Ranli Li Lina Wang Yong Xu Ziyao Cai Xueqin Song |
| author_sort | Chuanjun Zhuo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T07:28:17Z |
| format | Article |
| id | doaj.art-90d5f8e2c6e64f72aeaebbb267891d35 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-12T07:28:17Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-90d5f8e2c6e64f72aeaebbb267891d352022-12-22T00:33:05ZengNature Publishing GroupTranslational Psychiatry2158-31882022-06-011211610.1038/s41398-022-01999-7Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel targetChuanjun Zhuo0Feifei Zhao1Hongjun Tian2Jiayue Chen3Qianchen Li4Lei Yang5Jing Ping6Ranli Li7Lina Wang8Yong Xu9Ziyao Cai10Xueqin Song11Key Laboratory of Real Time Tracing Brain Circuit, Tianjin Medical Affiliated Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin Fourth HospitalKey Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples HospitalDepartment of Psychiatry, The Fourth Center Hospital of Tianjin Medical UniversityDepartment of Psychiatry, The Fourth Center Hospital of Tianjin Medical UniversityDepartment of Psychiatry, The Fourth Center Hospital of Tianjin Medical UniversityDepartment of Psychiatry, The Fourth Center Hospital of Tianjin Medical UniversityKey Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples HospitalKey Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples HospitalKey Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples HospitalDepartment of Psychiatry, The First Hospital of Shanxi Medical UniversityKey Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples HospitalDepartment of Psychiatry, First Affiliated Hospital of Zhengzhou UniversityAbstract 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.https://doi.org/10.1038/s41398-022-01999-7 |
| spellingShingle | Chuanjun Zhuo Feifei Zhao Hongjun Tian Jiayue Chen Qianchen Li Lei Yang Jing Ping Ranli Li Lina Wang Yong Xu Ziyao Cai Xueqin Song Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target Translational Psychiatry |
| title | Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target |
| title_full | Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target |
| title_fullStr | Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target |
| title_full_unstemmed | Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target |
| title_short | Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target |
| title_sort | acid sphingomyelinase ceramide system in schizophrenia implications for therapeutic intervention as a potential novel target |
| url | https://doi.org/10.1038/s41398-022-01999-7 |
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