ADAMTS4 Enhances Oligodendrocyte Differentiation and Remyelination by Cleaving NG2 Proteoglycan and Attenuating PDGFRa Signaling

Although NG2 is known to be selectively expressed in oligodendrocyte precursor cells (OPCs) for many years, its expressional regulation and functional involvement in oligodendrocyte differentiation have remained elusive. Here, we report that the sur-face-bound NG2 proteoglycan can physically bind to PDGF-AA and enhances PDGF receptor alpha (PDGFRa) activation of downstream signaling. During differentiation stage, NG2 protein is cleaved by A disintegrin and metalloproteinase with thrombospondin motifs type 4 (Adamts4), which is highly upregulated in differentiating OPCs but gradually downregulated in mature myelinating oligodendrocytes. Genetic ablation of Adamts4 gene impedes NG2 proteolysis, leading to elevated PDGFRa signaling but impaired oligodendrocyte differentiation and axonal myelination in both sexes of mice. Moreover, Adamts4 deficiency also lessens myelin repair in adult brain tissue following Lysophosphatidylcholine-induced demyelination. Thus, Adamts4 could be a potential therapeutic target for enhancing oligodendrocyte differentiation and axonal remyelination in demyelinating diseases.

Automated summary

In this study, it was discovered that NG2 proteoglycan can bind to PDGF-AA, enhancing PDGFRa signaling. Furthermore, the Adamts4 enzyme cleaves NG2 protein during the differentiation stage, with Adamts4 deficiency leading to impaired oligodendrocyte differentiation and axonal myelination. Additionally, Adamts4 deficiency also reduces myelin repair in the adult brain tissue. Overall, Adamts4 could be targeted for potential therapeutic strategies in demyelinating diseases.