Fig. 2

Pathophysiological mechanisms and underlying genetic aberrations that modulate MSA risk. The pathological hallmark of MSA is the presence of glial cytoplasmic inclusions. Our understanding of disease biology is inadequate, but purported mechanisms include ɑ-synuclein overexpression and accelerated uptake, oxidative stress, and microglial activation. These mechanisms are modulated by a range of genes, which have been shown to influence disease phenotype. This is further complicated by gene–gene interactions (e.g. IL-8 and ICAM-1), gene-environmental interactions (e.g. between COQ2 and organic solvents/pesticides) and epigenetics (e.g. DNA hypomethylation of SNCA). MSA-C Multiple System Atrophy (Cerebellar subtype), MSA-P Multiple System Atrophy (Parkinsonian subtype), MSA-Mixed Multiple System Atrophy (Mixed subtype)