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The central event in prion diseases is the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrPSc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrPC, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrPSc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrPSc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrPSc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrPSc during prion disease., Author Summary Shadoo is a protein that resembles the prion protein, which causes prion diseases such as Creutzfeldt-Jakob disease in humans and “mad cow” disease. In this paper, we demonstrate that during prion disease in animals, levels of Shadoo were reduced in the brain and correlated with levels of infectious prions. This phenomenon occurred following infection with 14 different prion strains but was not observed following the accumulation of other aggregated proteins, including those that cause Alzheimer's disease and Parkinson's disease. Thus, Shadoo levels in the brain are a specific indicator of prion disease status, and it may be possible to exploit this observation for diagnostic purposes. Although we show that Shadoo itself is unlikely to influence prion disease, using Shadoo as a tool to probe the biology of prions may be a useful strategy for deciphering how prions damage the brain.