UC San Diego

PrPC reportedly binds toxic oligomers and transduces toxic signals to advance neurodegeneration. However, the neurotoxic mechanism of PrPC signaling remains poorly understood. A new Prnp knock-in mouse model with a G93N substitution results in mice exhibiting severe kyphosis, ataxia, and seizures, with terminal disease observed as soon as postnatal day 25 (p25). Histologically, terminal brains display neurodegeneration and striking spongiform encephalopathy in the absence of aggregates. In this study, we assess how the addition of an N-terminal glycan to PrPC causes pathology in Prnp93N mice brains over time. Prnp93N brains were studied using immunohistochemistry (IHC) to label astrocytes, microglia, oligodendrocytes, oligodendrocyte precursors (OPCs), and neurons. Hematoxylin and eosin (HE) stains were used for scoring brain lesions to determine whether the Prnp93N mouse model develops spongiform encephalopathy (SE) consistent with bonefide prion disease. Starting at p15, the Prnp93N hippocampus and thalamus had a greater SE score compared to WT, and the SE scores increased gradually as the disease progressed. There were also prominent endothelial cells and neutrophils packed in the blood vessels of the Prnp93N hippocampi from p20-p25. IHC stains of Prnp93N hippocampi revealed a striking loss of CA1 pyramidal neurons as early as p20, and progressively worsening microgliosis and astrogliosis starting at p10. This thesis provides an in depth characterization of histopathology of the novel Prnp93N mouse model where G93N substitution in PrPC results in N-terminal-mediated toxic signaling that gives rise to the rapid onset of a developmental and spontaneous neurodegenerative disease in mice.