Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling

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.