p25α relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy

Abstract

p25{alpha} is an oligodendroglial protein that can induce aggregation of {alpha}-synuclein and accumulates in oligodendroglial cell bodies containing fibrillized {alpha}-synuclein in the neurodegenerative disease multiple system atrophy (MSA). We demonstrate biochemically that p25{alpha} is a constituent of myelin and a high-affinity ligand for myelin basic protein (MBP), and in situ immunohistochemistry revealed that MBP and p25{alpha} colocalize in myelin in normal human brains. Analysis of MSA cases reveals dramatic changes in p25{alpha} and MBP throughout the course of the disease. In situ immunohistochemistry revealed a cellular redistribution of p25{alpha} immunoreactivity from the myelin to the oligodendroglial cell soma, with no overall change in p25{alpha} protein concentration using immunoblotting. Concomitantly, an ~80% reduction in the concentration of full-length MBP protein was revealed by immunoblotting along with the presence of immunoreactivity for MBP degradation products in oligodendroglia. The oligodendroglial cell bodies in MSA displayed an enlargement along with the relocalization of p25{alpha}, and this was enhanced after the deposition of {alpha}-synuclein in the glial cytoplasmic inclusions. Overall, the data indicate that changes in the cellular interactions between MBP and p25{alpha} occur early in MSA and contribute to abnormalities in myelin and subsequent {alpha}-synuclein aggregation and the ensuing neuronal degeneration that characterizes this disease.