ASPH and CADASIL: The experimental approaches were driven by prior evidence that (1) insulin/IGF signaling regulates oligodendrocyte survival and function [27,28,29,30], (2) WM degeneration in human CADASIL has been linked to reduced insulin/IGF and Notch pathway signaling [58], (3) experimental chronic ethanol exposures lead to substantial impairments in oligodendrocyte function, myelin integrity, and myelin maintenance associated with inhibition of insulin/IGF signaling through survival and metabolic pathways [8,21, 70,76], and (4) ASPH functions via crosstalk with Notch networks including HIF-1α [54,57].