Pathogenesis of prion diseases

Prion diseases are rare neurological disorders that may be of genetic or infectious origin, but most frequently occur sporadically in humans. Their outcome is invariably fatal. As the responsible pathogen, prions have been implicated. Prions are considered to be infectious particles that represent mainly, if not solely, an abnormal, protease-resistant isoform of a cellular protein, the prion protein or PrP^C. As in other neurodegenerative diseases, aggregates of misfolded protein conformers are deposited in the CNS of affected individuals. Pathogenesis of prion diseases comprises mainly two equally important, albeit essentially distinct, topics: first, the mode, spread, and amplification of infectivity in acquired disease, designated as peripheral pathogenesis. In this field, significant advances have implicated an essential role of lymphoid tissues for peripheral prion replication, before a likely neural spread to the CNS. The second is the central pathogenesis, dealing, in addition to spread and replication of prions within the CNS, with the mechanisms of nerve cell damage and death. Although important roles for microglial neurotoxicity, oxidative stress, and complement activation have been identified, we are far from complete understanding, and therapeutic applications in prion diseases still need to be developed.