Astrocyte mitochondria: a substrate for iron deposition in the aging rat substantia nigra.
Little is currently known concerning the cellular substrates for, and the mechanisms mediating the pathological deposition of, redox-active brain 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 microanalytical techniques were used to demonstrate the existence of peroxidase-positive astroglia in the substantia nigra of adult rats. At 4 months of age and earlier, few GFAP-positive nigral astroglia contained small, electron-dense cytoplasmic inclusions which exhibited faint endogenous peroxidase activity (diaminobenzidine reaction product) and no detectable iron by microprobe analysis. In contrast, by 14-18 months of age, there was a significant, fourfold increase in numbers of peroxidase-positive astrocyte inclusions in the substantia nigra. The nigral gliosomes in the older animals were heterogeneously electron dense, immunoreactive for ubiquitin and a mitochondrial epitope, and often exhibited X-ray emission peaks for iron. Copper peaks were also detected in a minority of nigral gliosomes. Previous in vitro work indicated that the iron-mediated peroxidase activity in these cells promotes the bioactivation of dopamine and other catechols to neurotoxic free radical intermediates. Thus, mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to parkinsonism and other neurodegenerative disorders.
Schipper
H M
HM
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
Vininsky
R
R
Brull
R
R
Small
L
L
Brawer
J R
JR
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006651:Histocytochemistry; D007501:Iron / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000648:ultrastructure*
D005904:Glial Fibrillary Acidic Protein; D007501:Iron