Prion diseases are fatal degenerative disorders whose features include the accumulation of abnormal isoform of prion protein (PrPSc), vacuolation, and astrocytosis in the brain. After a prion infection, the cellular isoform of prion protein (PrPC) is converted into PrPSc, resulting in PrPC deficiency and PrPSc accumulation in the brain. These changes are major etiological events, thought to be closely related to the pathogenesis of prion diseases, and used as an index for diagnosis. Studies using recently developed research tools such as transgenic and knockout mice and cell lines have shown that the accumulation of PrPSc is not the sole factor contributing to the clinical onset of prion diseases and that loss-of function of PrPC by depletion leads to neuronal cell loss. Notably, PrPC plays an important role in anti-oxidative defense and its deficiency increases susceptibility to oxidative stress. Furthermore, there is a possible interrelationship between Alzheimer's disease and prion disease through loss-of-function of PrPC, which leads to the production of amyloid beta. In this review, we introduce research and diagnostic tools for prion diseases and the involvement of loss-of-function of PrPC in the pathogenicity of prion diseases.