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 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 adv

SUBMITTER: Bartoll A 

PROVIDER: S-EPMC7645369 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature