Immunohistochemical and biochemical studies demonstrate a distinct profileof alpha-synuclein permutations in multiple system atrophy

Although alpha-synuclein (alpha-syn) has been implicated as a major compone nt of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous an d contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to def ined regions throughout alpha-syn in immunohistochemical epitope mapping st udies of GCIs in MSA brains. Although the immunostaining profile of GCIs wi th these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in G CIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GC Is, but the entire panel of antibodies immunostained cortical Lewy bodies ( LBs) in dementia with LBs brain with similar intensity. While the distribut ion of alpha-syn labeled GCIs paralleled that previously reported using sil ver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a pr eviously undescribed burden of GCIs in the MSA hippocampal formation. Final ly, Western blots demonstrated detergent insoluble monomeric and high-molec ular weight alpha-syn species in GCI rich MSA cerebellar white matter. Coll ectively, these data indicate that alpha-syn is a prominent component of GC Is in MSA, and that GCIs and LBs may result from cell type specific conform ational or post-translational permutations in alpha-syn.