Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for α-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and α-synuclein immunoreactivity was measured in Western blots. Total α-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to α-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of α-synuclein. Surprisingly, the amount of SDS-soluble α-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble α-synuclein. These findings provide evidence that modifications of α-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.
