Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling
Abstract Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression...
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Springer Nature
2020-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911776 |
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| author | Adrián Bartoll Ana Toledano‐Zaragoza Josefina Casas Manuel Guzmán Edward H Schuchman María Dolores Ledesma |
| author_facet | Adrián Bartoll Ana Toledano‐Zaragoza Josefina Casas Manuel Guzmán Edward H Schuchman María Dolores Ledesma |
| author_sort | Adrián Bartoll |
| collection | DOAJ |
| description | Abstract Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses. |
| format | Article |
| id | doaj-art-a07b4ba9bc5b4fa6a8d2a758fb96efdc |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-a07b4ba9bc5b4fa6a8d2a758fb96efdc2025-08-20T04:03:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-10-01121112010.15252/emmm.201911776Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signalingAdrián Bartoll0Ana Toledano‐Zaragoza1Josefina Casas2Manuel Guzmán3Edward H Schuchman4María Dolores Ledesma5Centro Biologia Molecular Severo Ochoa (CSIC‐UAM)Centro Biologia Molecular Severo Ochoa (CSIC‐UAM)RUBAM, IQAC‐CSIC & CIBEREHDCentro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology, Complutense UniversityDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount SinaiCentro Biologia Molecular Severo Ochoa (CSIC‐UAM)Abstract Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses.https://doi.org/10.15252/emmm.201911776endocannabinoidsneurodegenerationNiemann–Picksphingomyelin |
| spellingShingle | Adrián Bartoll Ana Toledano‐Zaragoza Josefina Casas Manuel Guzmán Edward H Schuchman María Dolores Ledesma Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling EMBO Molecular Medicine endocannabinoids neurodegeneration Niemann–Pick sphingomyelin |
| title | Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| title_full | Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| title_fullStr | Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| title_full_unstemmed | Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| title_short | Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| title_sort | inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling |
| topic | endocannabinoids neurodegeneration Niemann–Pick sphingomyelin |
| url | https://doi.org/10.15252/emmm.201911776 |
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