Widespread alterations of alpha-synuclein in multiple system atrophy

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atro phy (MSA), a rare movement disorder frequently associated with autonomic dy sfunction. In this study of 21 cases of MSA, GCI were consistently immunore active for alpha-synuclein and double-immunostained for ubiquitin and oligo dendroglial markers, but not glial fibrillary acidic protein. No statistica lly significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and oliv opontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of M SA were fractionated according to solubility in buffer, Triton-X 100, sodiu m dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactiv ity was measured in Western blots, Total alpha-synuclein immunoreactivity w as increased in MSA compared to controls, with no statistically significant difference between SND and OPCA, Most of the increase was due to alpha-syn uclein in SDS fractions, In controls this fraction had little or no immunor eactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findin gs provide evidence that modifications of alpha-synuclein in MSA may be mor e widespread than obvious histopathology, Moreover, these alterations may c onstitute a biochemical signature for the synucleinopathies.