ASTROCYTE MITOCHONDRIA - A SUBSTRATE FOR IRON DEPOSITION IN THE AGINGRAT SUBSTANTIA-NIGRA

Little is currently known concerning the cellular substrates for, and the mechanisms mediating the pathological deposition of redox-active b rain iron in Parkinson's disease,In various subcortical brain regions, populations of astroglia progressively accumulate peroxidase-positive cytoplasmic inclusions derived from effete, iron-laden mitochondria. In the present study histochemical, ultrastructural, and elemental mic roanalytical techniques were used to demonstrate the existence of pero xidase-positive astroglia in the substantia nigra of adult rats. At 4 months of age and earlier, few GFAP-positive nigral astroglia containe d small, electron-dense cytoplasmic inclusions which exhibited faint e ndogenous peroxidase activity (diaminobenzidine reaction product) and no detectable iron by microprobe analysis. In contrast, by 14-18 month s of age, there was a significant, fourfold increase in numbers of per oxidase-positive astrocyte inclusions ire the substantia nigra. The ni gral gliosomes in the older animals were heterogeneously electron dens e, immunoreactive for ubiquitin and a mitochondrial epitope, and often exhibited X-say emission peaks for iron. Copper peaks were also detec ted in a minority of nigral gliosomes. Previous in vitro work indicate d that the iron-mediated peroxidase activity in these cells promotes t he bioactivation of dopamine and other catechols to neurotoxic free ra dical intermediates. Thus, mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the sen escent nervous system to parkinsonism slid other neurodegenerative dis orders. (C) 1998 Academic Press.