Cerebellar compartmentation of prion pathogenesis

Area of Science:

• Neuroscience
• Pathology
• Molecular Biology

Background:

• Prion diseases feature brain lesions influenced by prion strain, invasion route, and host factors.
• Understanding host cell-specific parameters is crucial for elucidating prion pathogenesis.
• The cerebellum's unique structure and cell types offer a model for studying these factors.

Purpose of the Study:

• To investigate the influence of prion strains on histopathological alterations in the mouse cerebellum.
• To identify host cell-specific factors contributing to prion disease lesion profiles.
• To explore the role of Purkinje cells and astrocytes in prion accumulation and neuroinflammation.

Main Methods:

• Histopathological analysis of mouse cerebellum infected with distinct prion strains (22L, ME7, 6PB1).
• Immunohistochemistry to detect prion protein (PrP) aggregation and identify zebrin expression in Purkinje cells.
• Assessment of Purkinje cell death, spongiosis, reactive gliosis, and astrocyte-specific markers (TNFR1).

Main Results:

• Distinct prion strains (PrP^22L, PrP^ME7) showed reproducible parasagittal banding patterns of accumulation in the cerebellar cortex.
• Prion aggregation patterns correlated with cerebellar compartmentation defined by zebrin expression in Purkinje cells.
• Zebrin-expressing Purkinje cells were more resistant to prion toxicity; zebrin-deficient Purkinje cells showed increased loss and spongiosis.
• Prion infection upregulated tumor necrosis factor-α receptor type 1 (TNFR1) in astrocytes near Purkinje cell synapses.

Conclusions:

• Purkinje cell sensitivity to prion insult is regionally restricted by cerebellar parasagittal compartmentation.
• Zebrin expression in Purkinje cells modulates prion toxicity and lesion patterns.
• Perisynaptic astrocytes, through TNFR1 upregulation, may contribute to prion pathogenesis and neuroinflammation.