期刊
EMBO MOLECULAR MEDICINE
卷 12, 期 11, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201911776
关键词
endocannabinoids; neurodegeneration; Niemann-Pick; sphingomyelin
资金
- Wylder Nation Foundation
- Spanish Ministry of Science and Education [SAF2017-87698-R]
- National Institutes of Health [2R37HD028607]
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 ofASMknockout (ASM-KO) mice and aASMDpatient. HighSMreduced expression of theeCBreceptorCB(1)in neuronal processes and induced its accumulation in lysosomes. Activation ofCB(1)receptor signaling, through inhibition of theeCB-degrading enzyme fatty acid amide hydrolase (FAAH), reducedSMlevels inASM-KOneurons. Oral treatment ofASM-KOmice with aFAAHinhibitor preventedSMbuildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also foundCB(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 ofFAAHinhibition to reduceSMand cholesterol levels inNPCpatient-derived cells and in the brain of aNPCmouse model. Our findings reveal a pathophysiological crosstalk between neuronalSMand theeCBsystem and offer a new treatment forASMDand other sphingolipidoses.
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