Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination

Abstract Myelin injury occurs in brain ageing and in several neurological diseases. Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPARγ in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPARγ and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood. Here, we identify PPARγ as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination/remyelination. Administration of pharmacological agonists of PPARγ not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPARγ function, either through the specific knockout of PPARγ in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPARγ agonists. At a mechanistic level, PPARγ induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination. In conclusion, our evidence reveals that PPARγ is a positive regulator of endogenous OPC differentiation and CNS myelination/remyelination and suggests that PPARγ and/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.