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Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM\u2010KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB\n                    <jats:sub>1<\/jats:sub>\n                    in neuronal processes and induced its accumulation in lysosomes. Activation of CB\n                    <jats:sub>1<\/jats:sub>\n                    receptor signaling, through inhibition of the eCB\u2010degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM\u2010KO neurons. Oral treatment of ASM\u2010KO 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 CB\n                    <jats:sub>1<\/jats:sub>\n                    receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann\u2013Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient\u2010derived 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.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201911776","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T06:23:37Z","timestamp":1601879017000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling"],"prefix":"10.1038","volume":"12","author":[{"given":"Adri\u00e1n","family":"Bartoll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Toledano\u2010Zaragoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josefina","family":"Casas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Guzm\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward H","family":"Schuchman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5679-6891","authenticated-orcid":false,"given":"Mar\u00eda Dolores","family":"Ledesma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,5]]},"reference":[{"key":"BFEMMM201911776_CR1","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1517\/17460440903018857","volume":"4","author":"K Ahn","year":"2009","unstructured":"Ahn K, Johnson DS, Cravatt BF (2009) Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. 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