Regional and cellular iron deposition patterns predict clinical subtypes of multiple system atrophy

Abstract Background Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its reciprocal relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. In this regard, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology. Methods We performed the first cell type (α-synuclein-affected and -unaffected neurons, astroglia, oligodendrocytes, and microglia)-specific evaluation of MSA iron deposition in the globus pallidus (GP), putamen, and the substantia nigra (SN), using a combination of iron staining with immunolabelling on human post-mortem MSA brains. We evaluated selective regional and cellular vulnerability patterns to iron deposition distinctly in MSA-parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes and explored possible underlying molecular pathways by mRNA expression analysis of key iron- and the closely related oxygen-homeostatic genes. Results MSA-P and MSA-C showed a distinct pattern of regional iron burden across the subcortical nuclei. We identified microglia as the major cell type accumulating iron in these regions of MSA brains, which was more distinct in MSA-P. MSA-C showed a more heterogenous cellular iron accumulation, in which astroglia showed greater or similar accumulation of iron. Notably, iron deposition was found outside the cellular bodies in the same regions and cellular iron burden minimally correlated with α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen, rather than of cellular iron, homeostatic genes. Importantly, hierarchal cluster analysis revealed pattern of cellular vulnerability to iron accumulation, rather than of α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes. Conclusions We identified distinct regional, and for the first time, cellular distribution of subcortical iron deposition in MSA-P and MSA-C, and revealed cellular vulnerability pattern to iron deposition as a novel neuropathological characteristic that predicts MSA subtypes, distinctly from α-synuclein pathology. These findings support the role of iron dysregulation as an early effector of disease pathology in MSA. Our findings suggesting distinct iron-related pathomechanisms in MSA subtypes inform current efforts in iron chelation therapies at the disease and cellular-specific levels.