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.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
H M
HM
Schipper
R
R
Vininsky
R
R
Brull
L
L
Small
J R
JR
Brawer
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