Open AccessInhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling
Author(s) -
Bartoll Adrián,
ToledanoZaragoza Ana,
Casas Josefina,
Guzmán Manuel,
Schuchman Edward H,
Ledesma María Dolores
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911776
Subject(s) - fatty acid amide hydrolase , acid sphingomyelinase , endocannabinoid system , anandamide , sphingomyelin , ceramide , microbiology and biotechnology , lipid signaling , sphingomyelin phosphodiesterase , hydrolase , chemistry , biochemistry , biology , enzyme , cannabinoid receptor , receptor , membrane , apoptosis , agonist
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 CB 1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB 1 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 CB 1 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.