Despite several decades of dedicated research by a diverse array of researchers from around the globe, the molecular mechanisms underlying neuronal loss during transmissible spongiform encephalopathy (TSE) remain to be elucidated. Additionally, the etiology of so-called "sporadic" cases of TSE, which represents the vast majority of cases in both humans and animals, remains unknown. Several recent advancements in the understanding of other protein misfolding neurodegenerative disorders including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosi (ALS), and TSE have highlighted the similarities between disease etiopathogenesis which may broaden the diversity of potential future therapies. As our understanding of each disease state increases, the potential of advancements from one disease state applying to another is tantalizingly possible. Conversely, the public health implications of the discovery that AD, PD, and ALS may be transmitted in a prion-like manner highlight the urgency in elucidating the mechanisms underlying these devastating disorders. Although the metal binding capacity of PrP^C and other amyloidogenic proteins is well documented, the environmental contribution to TSE pathogenesis, including the role of divalent metals such as manganese, is unknown. Herein we report that neuronal cells infected with TSE are less susceptible to Mn-induced toxicity than uninfected cells. Mn treatment also induces cytosolic localization of PrP^C in cell and animal models, thus providing a mechanism that incorporates inhibition of the protein degradation machinery with metal dyshomeostasis. Additionally, we have discovered proteolytic activation of the delta isoform of protein kinase C (PKCδ) and changes in the phosphorylation of PKCδ at two regulatory sites in multiple brain regions in a mouse-adapted scrapie model. Knockout of PKCδ causes a significant delay in the onset of motor symptoms associated with TSE and an altered pattern of oxidative damage. These discoveries provide further mechanistic insight into TSE-related neuronal degeneration.