EFFECT OF NEUROTOXIC METAL-IONS IN-VITRO ON PROTEOLYTIC-ENZYME ACTIVITIES IN HUMAN CEREBRAL-CORTEX

In order to develop a clearer understanding of the role of aberrant pr otein turnover in the pathogenesis of neurodegenerative disorders, the effect of a series of potentially neurotoxic metal ions on a wide ran ge of proteases (lysosomal and cytoplasmic proteinases and peptidases) from human cerebral cortex was determined in vitro. The response of l ysosomal and cytoplasmic proteases to inhibition by metal ion species (0.05-5 mmol/l) was broadly similar; Sr2+, Mg2+, Ba2+ or Ca2+ showed l ittle inhibitory effect at any concentration for most protease types, whilst Cu2+, Cd2+, Pb2+, Mg2+ or Zn2+ showed a substantial degree of i nhibition, depending on metal ion concentration and enzyme type. Ca2activated neutral proteinases were no more susceptible to general meta l ion inhibition than most other protease types. Some proteases showed marked activation of activity in the presence of several metal ion sp ecies. Both lysosomal and cytoplasmic proteases were relatively insens itive to inhibition by Al3+ compared with that obtained with other met al ion species. It is of note that cathepsin D was particularly resist ant to inhibition by most metal ion species, whilst pyroglutamyl amino peptidase was particularly susceptible to inhibition by low concentrat ions of many metal ions. The above data suggest that in considering th e potential role of neurotoxic metal ions in the pathogenesis of neuro degenerative disorders of the CNS (via protease inhibition in the intr acellular protein degradation pathway), attention should be focused on the interactions between a wide range of metal ion species and protea se types, rather than be restricted to the Al3+/calpain system (as is presently the case in Alzheimer's disease research). In particular, th e potential role of pyroglutamyl aminopeptidase in intracellular prote in degradation (in addition to more specialized functions such as neur otransmitter processing) and the pathological consequences of the susc eptibility of this enzyme to inhibition by neurotoxic metal ions requi res further investigation.