SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligo-dendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow genera-tion of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasmamembrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface andthus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecu-lar mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better under-standing of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, wedemonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located atthe C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex andwhose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma mem-brane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linkeddown-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease inGPR171cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leadingto hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and thatdisruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects.