Multiple system atrophy: α-Synuclein strains at the neuron-oligodendrocyte crossroad

The aberrant accumulation of alpha-Synuclein within oligodendrocytes is an enigmatic, pathological feature specific to Multiple system atrophy (MSA). Since the characterization of the disease in 1969, decades of research have focused on unravelling the pathogenic processes that lead to the formation of oligodendroglial cytoplasmic inclusions. The discovery of aggregated alpha-Synuclein (alpha-Syn) being the primary constituent of glial cytoplasmic inclusions has spurred several lines of research investigating the relationship between the pathogenic accumulation of the protein and oligodendrocytes. Recent developments have identified the ability of alpha-Syn to form conformationally distinct"strains" with varying behavioral characteristics and toxicities. Such "strains" are potentially disease-specific, providing insight into the enigmatic nature of MSA. This review discusses the evidence for MSA-specific alpha-Syn strains, highlighting the current methods for detecting and characterizing MSA patient-derived alpha-Syn. Given the differing behaviors of a-Syn strains, we explore the seeding and spreading capabilities of MSA-specific strains, postulating their influence on the aggressive nature of the disease. These ideas culminate into one key question: What causes MSA-specific strain formation? To answer this, we discuss the interplay between oligodendrocytes, neurons and alpha-Syn, exploring the ability of each cell type to contribute to the aggregate formation while postulating the effect of additional variables such as protein interactions, host characteristics and environmental factors. Thus, we propose the idea that MSA strain formation results from the intricate interrelation between neurons and oligodendrocytes, with deficits in each cell type required to initiate alpha-Syn aggregation and MSA pathogenesis.