ABSTRACT
The hallmark event in transmissible spongiform encephalopathies (TSEs) is the misfolding and aggregation of the prion protein (PrP) into a β-sheet-rich oligomeric structure that, by a not-yet-completely understood mechanism, produces brain degeneration. Misfolding and aggregation of PrP is also the basis by which the prion infectious agent (PrPSc) replicates in the body. Strikingly, a very similar molecular event is the hallmark process in a variety of human disorders, including the most prevalent neurodegenerative diseases and several systemic amyloidoses [Kelly, 1996; Carrell and Gooptu, 1998; Soto, 2001; Dobson, 2001]. These diseases, grouped under the name of protein misfolding disorders (PMD), are thought to arise from the misfolding and aggregation of an underlying protein. Recent findings strongly support this hypothesis and have increased our understanding of the molecular mechanism of PMD [Soto, 2001; Soto, 2003]. This chapter describes the clinical, etiological, and pathological features of these diseases, overviews the evidence in favor of protein misfolding as the key event in the disease pathogenesis, and discusses the molecular and structural basis underlying this process.
