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p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy
Yun Ju C Song1, Ditte M S Lundvig, Yue Huang
1Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia.
Abstract:
p25alpha 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 p25alpha is a constituent of myelin and a high-affinity ligand for myelin basic protein (MBP), and in situ immunohistochemistry revealed that MBP and p25alpha colocalize in myelin in normal human brains. Analysis of MSA cases reveals dramatic changes in p25alpha and MBP throughout the course of the disease. In situ immunohistochemistry revealed a cellular redistribution of p25alpha immunoreactivity from the myelin to the oligodendroglial cell soma, with no overall change in p25alpha protein concentration using immunoblotting. Concomitantly, an approximately 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 p25alpha, 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 p25alpha occur early in MSA and contribute to abnormalities in myelin and subsequent alpha-synuclein aggregation and the ensuing neuronal degeneration that characterizes this disease.
Insights
Changes in myelin proteins p25alpha and myelin basic protein (MBP) occur early in multiple system atrophy (MSA). These alterations in oligodendroglial cells contribute to alpha-synuclein aggregation and neurodegeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Protein Biochemistry
Background:
- p25alpha is an oligodendroglial protein implicated in alpha-synuclein aggregation.
- Multiple system atrophy (MSA) is a neurodegenerative disease characterized by alpha-synuclein accumulation in oligodendroglial cells.
Purpose of the Study:
- To investigate the role of p25alpha and its interaction with myelin basic protein (MBP) in MSA.
- To understand the early molecular changes in oligodendroglia during MSA pathogenesis.
Main Methods:
- Biochemical assays to determine p25alpha's association with myelin and MBP.
- In situ immunohistochemistry to visualize protein localization in normal and MSA brains.
- Immunoblotting to quantify protein concentrations and detect degradation products.
Main Results:
- p25alpha is a high-affinity ligand for MBP and colocalizes with MBP in myelin.
- In MSA, p25alpha redistributes from myelin to oligodendroglial cell bodies.
- MSA brains show reduced full-length MBP and accumulation of MBP degradation products in oligodendroglia.
- Oligodendroglial cell enlargement and p25alpha relocalization are enhanced by alpha-synuclein deposition.
Conclusions:
- Altered interactions between MBP and p25alpha are early events in MSA.
- These changes contribute to myelin abnormalities and alpha-synuclein aggregation.
- The findings suggest a role for myelin pathology in MSA-related neurodegeneration.
