[Neuronal cell death and intracellular proteinase functions]

Recently, attention has been paid to intracellular proteinase functions in relation to the process of neuronal cell death, and defining how they are involved is essential for developing neuroprotective strategies as well as for understanding the pathology of neurodegenerative diseases. Several recent articles have outlined the activation and deleterious effect of mu-calpain, a calcium-activated cysteine proteinase, on the cytoskeleton protein network, which is thought to lead to cell death. Furthermore, a marked increase in cathepsins B, L, and D, lysosomal proteinases, and cathepsin E, non-lysosomal aspartic proteinase, in neurons has been shown in the early stage of neuronal degeneration. The increased levels of these lysosomal cathepsins in degenerating neurons are considered to be associated with stimulated autophagy, which occasionally can lead to neuronal cell death. The molecular form of cathepsin E accumulated in affected neurons was different from that of the normal cathepsin E molecule. This unusual molecular form of cathepsin E is likely to be critical for disruption of normal cellular function, possibly culminating in neuronal cell death. The increased level of such proteinases was also found in reactive glial cells. In these cells, cathepsin E was increased as a mature form exclusively in reactive microglial cells, while cathepsins D and G were increased mainly in reactive astrocytes. Overproduction of cathepsins E, D and G in these reactive glial cells may be finally involved in the pathogenesis of neuro-degenerative disease.