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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Developmental expression of the prion protein gene in glial cells
1Brain Research Institute, University of Zurich, Switzerland.
Abstract:
Replication of prions is dependent on the presence of the host protein PrPc. During the course of disease, PrPc is converted into an abnormal isoform, PrPSc, which accumulates in the brain. Attempts to identify the cell type(s) in which prion replication and PrP conversion occur have reached conflicting results. Although PrP mRNA is present in high amounts in neurons throughout the life of the animal, PrPSc initially accumulates in astrocytes and possibly other glial cells and, later in the course of the disease, spreads diffusely in the tissue, often in white matter. We report here that PrP mRNA is expressed not only in neurons but also in astrocytes and oligodendrocytes throughout the brain of postnatal hamsters and rats. The level of glial Prp mRNA expression in neonatal animals was comparable to that of neurons and increased two-fold during postnatal development. A substantial portion of brain PrP mRNA is therefore contributed by glial cells. Our results provide an explanation for the accumulation of PrPSc in white matter tissue and in the cytoplasm of glial cells and argue for a direct involvement of glia in prion propagation.
Insights
Glial cells, including astrocytes and oligodendrocytes, express prion protein (PrP) mRNA in the brain. This glial expression contributes significantly to prion propagation and explains PrPSc accumulation in white matter and glial cells.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Diseases
Background:
- Prion replication relies on the host protein PrPc, which converts to the abnormal PrPSc isoform during disease.
- Previous studies yielded conflicting results regarding the specific cell types involved in prion replication and PrP conversion.
- PrPSc accumulation is observed in astrocytes and glial cells, particularly in white matter, despite high neuronal PrP mRNA levels.
Purpose of the Study:
- To investigate the expression of prion protein (PrP) mRNA in glial cells during postnatal development.
- To determine the contribution of glial cells to the overall brain PrP mRNA pool.
- To elucidate the role of glial cells in prion propagation and PrPSc accumulation.
Main Methods:
- Quantitative analysis of PrP mRNA expression in neurons, astrocytes, and oligodendrocytes in postnatal hamster and rat brains.
- Comparison of glial PrP mRNA levels between neonatal and developing animals.
Main Results:
- PrP mRNA is expressed in astrocytes and oligodendrocytes, in addition to neurons, throughout the brain.
- Glial PrP mRNA expression levels in neonates are comparable to neuronal levels and increase twofold during development.
- Glial cells contribute a substantial portion of the total brain PrP mRNA.
Conclusions:
- Glial cells, including astrocytes and oligodendrocytes, are direct participants in prion propagation.
- The expression of PrP mRNA in glial cells provides a molecular basis for PrPSc accumulation in white matter and glial cytoplasm.
- These findings challenge the neuron-centric view of prion diseases and highlight the role of glia.
