Accumulation of 14-3-3 proteins in glial cytoplasmic inclusions in multiple system atrophy

Glial cytoplasmic inclusions are the pathological hallmark of multiple system atrophy. However, the molecular mechanisms underlying the formation of glial cytoplasmic inclusions remain unclear. Alpha-synuclein, a major component of glial cytoplasmic inclusions, has the ability to interact with 14-3-3 proteins, which mediate several types of signal transduction pathways. To elucidate the role of these 14-3-3 proteins in patients with multiple system atrophy, we performed immunohistochemical studies on 14-3-3 in brain tissue specimens from 7 control subjects and from 15 patients with multiple system atrophy. In both control and multiple system atrophy cases, 14-3-3 immunoreactivity was observed mainly in the neuronal somata and proximal processes, as well as the nerve fibers. Even in the severely affected regions of patients with multiple system atrophy, 14-3-3 immunoreactivity generally was spared in the surviving neurons, some of which were strongly immunolabeled. In addition, numerous glial cytoplasmic inclusions were intensely immunostained, and neuronal cytoplasmic inclusions and dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest that an aberrant accumulation of 14-3-3 proteins may occur in brains affected by multiple system atrophy, and that 14-3-3 proteins may be associated with the pathogenesis of multiple system atrophy.