Oligodendroglia and myelin pathology in fragile X syndrome

Studies of the pathophysiology of fragile X syndrome (FXS) have predominantly focused on synaptic and neuronal disruptions in the disease. However, emerging studies highlight the consistency of white matter abnormalities in the disorder. Recent investigations using animal models of FXS have suggested a role for the fragile X translational regulator 1 protein (FMRP) in the development and function of oligodendrocytes, the myelinating cells of the central nervous system. These studies are starting to uncover FMRP's involvement in the regulation of myelin-related genes, such as myelin basic protein, and its influence on the maturation and functionality of oligodendrocyte precursor cells and oligodendrocytes. Here, we consider evidence of white matter abnormalities in FXS, review our current understanding of FMRP's role in oligodendrocyte development and function, and highlight gaps in our knowledge of the pathogenic mechanisms that may contribute to white matter abnormalities in FXS. Addressing these gaps may help identify new therapeutic strategies aimed at enhancing outcomes for individuals affected by FXS.image The review article by Hourani and Pouladi explores how oligodendrocytes and the myelin they produce are implicated in fragile X syndrome (FXS), a major genetic cause of intellectual disability and autism. While most research on FXS has focused on how neurons are affected, this review highlights the notable alterations in brain white matter in FXS individuals and animal models. It discusses the role of Fragile X Messenger Ribonucleoprotein 1 (FMRP), whose loss causes FXS, in oligodendrocyte development and function, exploring potential mechanisms of oligodendroglial dysfunction as well as new research directions that could pave the way for innovative treatments.image