Unveiling mechanisms underlying oligodendrocyte differentiation: new perspectives for the treatment of neurological diseases

Defective myelination has recently been associated to a number of neurological disorders, including multiple sclerosis, Alzheimer’s disease, schizophrenia, depression and Down syndrome. Thus, to study the mechanisms underlying OL development may be a good strategy to develop new approaches for the treatment of these pathologies. To this aim, a good pharmacological candidate is the G protein-coupled receptor GPR17, which has been proposed to act as a regulator of OL development, maintaining differentiating oligodendrocyte precursors (OPCs) into a pre-myelinating state. GPR17 down-regulation is required to allow cells to enter the terminal phases of maturation. To understand the processes that regulate GPR17 signaling we focused on the mechanisms that control its expression at the plasma membrane. At first, we demonstrated that after endocytosis GPR17 is sorted to lysosomes or recycled to the cell surface via a Rab4-dependent pathway. To further characterize GPR17 sorting, we analyzed the role of its C-terminal PDZ binding motif and, using a combination of biochemical and cell biology approaches, we demonstrated that it is required for receptor recycling to the plasma membrane by means of an interaction with retromer complex-associated protein SNX27. Interestingly, SNX27 knockdown increases GPR17 degradation while accelerating cell terminal maturation. Since recent studies in Down syndrome (DS) revealed that overexpression of trisomic mir155 results in SNX27 down-regulation, we thought it interesting to analyze OL differentiation in Ts65Dn murine model of DS. Our data indicated an altered differentiation of OLs in DS mice brains, and myelination defects. This prompts us to further investigate the role of mir155 in OL differentiation. Preliminary data indicate that oligodendroglial cells express low levels of mir155 while mir155 overexpression results in an overall inhibition of OL differentiation via a mechanism that does not depend only on SNX27 inhibition. Further analysis is ongoing to understand the mechanisms involved in mir155-associated myelination defects.