Mechanisms of neuronal death in transmissible spongiform encephalopathies

The premature primary death of nerve cells is a basic feature of transimissible spongiform encephalopathies (TSEs) or prion diseases and other neurodegenerative disorders, although the cellular pathways leading to this neuronal loss are not entirely clear. Moreover, the question of whether there is a direct relation between the deposits of PrP(d) and the loss of neurons still remains a matter for conjecture. According to established classification, three types of programmed cell death during morphogenesis are discriminated: (1) apoptosis, (2) autophagy and (3) cytoplasmic cell death. Apoptosis has become the most popular concept of cell death in neurodegeneration. However, there is no direct and convincing evidence of apoptosis of nerve cells in most neurodegenerative diseases. Although there is strong evidence that autophagy is a common ultrastructural feature of TSEs, it is still unclear how the autophagy contributes to the overall pathology and, especially, to the neuronal loss underlying prion diseases. There are no data on cytoplasmic cell death in prion diseases. The contrasting data and lack of consistent molecular basis of some types of cell death leave unanswered the question of which type of cell death is responsible for neuronal loss in TSEs. However, recently developed techniques and the careful examination of the molecular processes leading to different types of cell death should provide the answer in future.