Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency

Abstract

Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms. This study shows that sphingomyelin-induced impairment of oligodendrocyte (OL) differentiation and myelin alterations are early pathological events in acid sphingomyelinase deficiency (ASMD) and can be ameliorated by pharmacological inhibition of the extracellular matrix receptor CD44. Reduced myelin area, increased myelin debris, increased numbers of immature OLs, and reduced numbers of mature OLs are pathological hallmarks in the cerebellum of ASMko mice, a model of neurological ASMD. High sphingomyelin levels impair the morphological differentiation of cultured OLs. Transcriptomic analysis reveals an overlap between OL precursor cell and mature OL gene expression profiles in ASMko mice. CD44, which is physiologically downregulated to permit OL maturation, is aberrantly upregulated in mature OLs from ASMko mice. Inhibition of CD44 with Verbascoside in cultured ASMko OLs and in ASMko mice rescues OL maturation, ameliorates myelin abnormalities, and improves motor behavior. Reduced myelin area, increased myelin debris, increased numbers of immature OLs, and reduced numbers of mature OLs are pathological hallmarks in the cerebellum of ASMko mice, a model of neurological ASMD. High sphingomyelin levels impair the morphological differentiation of cultured OLs. Transcriptomic analysis reveals an overlap between OL precursor cell and mature OL gene expression profiles in ASMko mice. CD44, which is physiologically downregulated to permit OL maturation, is aberrantly upregulated in mature OLs from ASMko mice. Inhibition of CD44 with Verbascoside in cultured ASMko OLs and in ASMko mice rescues OL maturation, ameliorates myelin abnormalities, and improves motor behavior. This study shows that sphingomyelin-induced impairment of oligodendrocyte (OL) differentiation and myelin alterations are early pathological events in acid sphingomyelinase deficiency (ASMD) and can be ameliorated by pharmacological inhibition of the extracellular matrix receptor CD44.