Bovine spongiform encephalopathy (BSE) is a fatal transmissible spongiform encephalopathy caused by the misfolding of the host prion protein (PrP), representing a unique intersection between molecular pathology, neuroanatomy, and public health regulation. Although historically framed as a single feedborne epizootic, BSE is now recognized as a spectrum of strain-defined prion disorders encompassing classical and atypical forms with distinct origins, neuroanatomical trajectories, and surveillance implications. This review integrates advances in prion biology, neurodegenerative mechanisms, and anatomical pathways of neuroinvasion to reframe BSE as a heterogeneous disease entity. We synthesize evidence on PrPC structure, trafficking, and proteolytic processing to explain how normal cellular physiology enables strain-specific conversion to pathogenic PrPSc and subsequent neurotoxicity. Distinct patterns of neuroinvasion and regional vulnerability are discussed for classical versus atypical (H- and L-type) BSE, highlighting differences in lymphoid involvement, brainstem targeting, and cortical or cerebellar tropism. We further examine how these biological differences translate into diagnostic sensitivity, surveillance design, and zoonotic risk assessment. By integrating molecular strain diversity with neuroanatomical connectivity, this review underscores the limitations of obex-centered surveillance for atypical BSE and emphasizes the need for proportionate yet precautionary monitoring strategies. These considerations should be interpreted in light of surveillance-dependent detection biases, which influence the apparent distribution of BSE forms. Ultimately, BSE emerges as a critical model for understanding how protein misfolding disorders bridge cellular mechanisms, animal health, and human public health policy.
Marzola et al. (Sat,) studied this question.