Immunohistochemical and Biochemical Studies Demonstrate a Distinct Profile of α-Synuclein Permutations in Multiple System Atrophy

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Abstract
Although α-synuclein (α-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length α-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout α-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the α-syn epitopes detected in GCIs. Notably, carboxy-terminal α-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of α-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal α-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight α-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that α-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in α-syn.