MOLECULAR BASIS OF SPONGIFORM ENCEPHALOPATHY IN PRION DISEASE

During prion disease, aggregated prion protein spreads rapidly throughout the central nervoussystem, inciting neuronal vacuolation, dystrophic neurites, and ultimately neuronal death.Neuronal expression of the cellular prion protein (PrPC) is required for triggering neuronal deathpathways, yet how prions induce neuronal vacuolation and dystrophic neurites is unclear. Wehave developed a new knock-in mouse model of spongiform encephalopathy due to a singleamino acid substitution in the amino terminus of PrPC. Mice develop severe spongiformdegeneration and dystrophic neurites, particularly in the hippocampus, and the disease onset isdelayed by the co-expression of wild type PrPC. Autophagy-related protein levels are altered inthe brain and spinal cord and are similarly altered in infectious prion disease. We aim todecipher the aberrant molecular pathways in this mouse model of spongiform encephalopathy.In Specific Aim 1, we will define the altered cellular and biochemical features associated withspongiform encephalopathy in the transgenic mice during aging. In Specific Aim 2, we willdetermine the dysregulated endolysosomal signaling pathways that lead to neuronaldegeneration, comparing findings with infectious prion disease in mice and sporadic Creutzfeldt-Jakob disease in humans. These studies are the first to target the origin of spongiformdegeneration and dystrophic neurites in a knock-in mouse model expressing mutated PrP, andare expected to help define the molecular pathways inciting neuronal death in prion disease.