Alpha-synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy

Abstract

Multiple system atrophy (MSA) belongs to synucleinopathies and is characterized pathologically by oligodendroglial inclusions (GCIs) composed of 20- to 30-nm tubular filaments. α-Synuclein fibrils formed in vitro, however, range between 10 and 12 nm in diameter. To understand the relationship between α-synuclein and GCI filaments, we conducted structural analyses of GCIs in fixed brain sections and isolated from fresh-frozen MSA brains. In fixed brain sections, GCIs were composed of amorphous material-coated filaments up to 30 nm in size. The filaments were often organized in parallel bundles extending into oligodendroglial processes. In freshly isolated GCIs, progressive buffer washes removed amorphous material and revealed that GCI filaments consisted of 10-nm-sized central core fibrils that were strongly α-synuclein immunoreactive. Image analysis revealed that each core fibril was made of two subfibrils, and each subfibril was made of a string of 3- to 6-nm-sized particles probably α-synuclein oligomers. Immunogold labeling demonstrated that epitopes encompassing entire α-synuclein molecule were represented in the core fibrils, with the N-terminal 11–26 and C-terminal 108–131 amino acid residues most accessible to antibodies, probably exposed on the surface of the fibril. Our study indicates that GCI filaments are multilayered in structure, with α-synuclein oligomers forming the central core fibrils of the filaments.