Cellular and Molecular Mechanisms of Prion Disease

Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathologic features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably-sized aggregated prion protein ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here we explore recent advances, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells, and the effect of prion conformation on spreading pathways. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.