In contrast to acute lesions, there is consensus of significant oligodendroglial cell loss in the center of chronic active lesions as indicated by neuropathological observations of post-mortem tissue8 and single nuclei sequencing47. However, although a number of studies have tried to identify the pathways involved, the precise mechanisms of OL death remain to be established and are being investigated in ongoing studies using experimental in vivo and in vitro models. An increasing number of regulated cell death mechanisms are being defined by their distinct molecular signatures, and linked to specific inducing signals or conditions (Fig. 2). These pathways can be triggered by specific receptor engagement, such as by immune/infectious constituents and/or by metabolic insults, all of which are implicated in the MS disease process. For instance, apoptosis can be triggered by inflammatory signals or metabolic stress. However, Prineas and Barnett observed in two secondary-progressive MS cases that surviving OLs present amongst the microglia and macrophages at the lesion edge rarely showed apoptotic nuclei48.
