Nuclear BIN1 isoforms regulate c-Myc-mediated cell cycle control in oligodendrocytes

Bridging integrator 1 (BIN1) is a nucleocytoplasmic protein that inhibits c-Myc and acts as a tumour suppressor. BIN1 is ubiquitously expressed, but it is most abundant in skeletal myocytes and brain oligodendrocytes (OLs). As its variants confers the second strongest risk to sporadic Alzheimer's disease (AD), BIN1 expression in OL lineage is of particular interest, given the loss of myelin integrity is highly correlated with the progress of sporadic AD. However, the nucleocytoplasmic localisation and the modulation of the alternative splicing of the 20 exons of BIN1 in OLs. are poorly understood. We characterised BIN1 isoforms expression in OLs from two independent cohorts of postmortem AD brains using immunoblotting and immunohistochemistry and extended the findings to experimental APP/PS1 mice and primary OL cultures. Neuronal isoforms of BIN1 (BIN1:H, 95kDa) were significantly reduced (P < 0.0001), and the white matter/OL-specific isoforms (BIN1:L, 70kDa) were increased (P = 0.0349) in AD cases and APP/PS1 mice. Importantly, the OL-specific BIN1 isoforms, identified by three different antibodies, were found in the nucleus of OL in human and mouse. Nuclear BIN1 was expressed by both the OL progenitor cell (OPC) and mature OL in vitro. Silencing Bin1 in OPCs perturbed the p53 pathway and a transcriptomic shift in cell cycle regulation, consistent with reduced Bin1-mediated c-Myc inhibition. The putative interacting sites between OL-specific BIN1:L and c-Myc was also identified by in silico analysis. Together, the present study establishes nuclear BIN1 as a regulator of OL cell cycle control and support hypothesis that nuclear BIN1 dysfunction in OL may contribute mechanistically to myelin pathology in sporadic AD.